Aryl dihydropyridinones and piperidinone MGAT2 inhibitors

ABSTRACT

The present invention provides compounds of Formula (I): 
                         
or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are monoacylglycerol acyltransferase type 2 (MGAT2) inhibitors which may be used as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/867,825, filed Jan. 11, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/488,642, filed Apr. 17, 2017, now U.S. Pat. No.9,901,572, which is a continuation of U.S. application Ser. No.14/883,067, filed on Oct. 14, 2015, now U.S. Pat. No. 9,663,466, issuedMay 30, 2017, which is a continuation of U.S. application Ser. No.14/305,098 filed on Jun. 16, 2014, now U.S. Pat. No. 9,187,424, issuedNov. 17, 2015, which is a continuation of U.S. application Ser. No.13/688,584 filed on Nov. 29, 2012, now U.S. Pat. No. 8,791,091, issuedJul. 19, 2014, which claims the priority benefit of U.S. ProvisionalApplication No. 61/566,039, filed Dec. 2, 2011; the contents of whichare herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention provides novel aryl dihydropyridinone andpiperidinone compounds, and their analogues thereof, which are MGAT2inhibitors, compositions containing them, and methods of using them, forexample, for the treatment or prophylaxis of diabetes, obesity,dyslipidemia and related conditions.

BACKGROUND OF THE INVENTION

The prevalence of obesity and diabetes is increasing at an alanningrate. According to WHO, in 2008, 70% of the U.S. adult population wasoverweight, and among them 33% were obese. Parallel to the explosivenumber of people becoming overweight and obese, in 2008, it wasestimated that 12.3% of the U.S. population had elevated blood glucose[http://www.who.int/diabetes/facts/en/]. The obesity/diabetes epidemicis not unique to the U.S. According to WHO (Fact Sheet No. 312,September 2012), 347 million people worldwide have diabetes. Treatingobesity and improving glycemic control effectively and safely remainmajor challenges for modern medicine.

Monoacylglycerol acyltransferase 2 (MGAT2) has emerged as an attractivetarget for the treatment of obesity and type II diabetes [Yen, C. L. etal., Nat. Med., 15(4):442-446 (2009)]. MGAT2 is highly and selectivelyexpressed in the small intestine where it exerts a pivotal role in themonoacylglycerol-pathway for the absorption of dietary fat. When dietaryfat is ingested, pancreatic lipase digests triglycerides into free fattyacids and 2-monoacylglycerol, which are absorbed by intestinalepithelial enterocytes. Once inside enterocytes, free fatty acids and2-monoacylglycerol are used as building blocks to resynthesizetriglycerides by two sequential acylation steps; first by MGAT and thenby DGAT enzyme reactions. Triglycerides are then incorporated intochylomicrons and secreted into lymph to be utilized as an energy supplyfor the body. MGAT2 knockout mice exhibit a healthy metabolic phenotypeand show resistance to high-fat diet induced obesity, improvement ininsulin sensitivity and decreased fat accumulation in liver and adiposetissue. In addition, genetic deletion of MGAT2 produces mice withincreased levels of GLP1 [Yen, C. L. et al., Nat. Med., 15(4):442-446(2009)]. Taken together, these data show that MGAT2 inhibitors holdpromise to treat metabolic disorders such as obesity, type II diabetesand dyslipidemia.

SUMMARY OF THE INVENTION

The present invention provides aryl dihydropyridinone and piperidinonecompounds, and their analogues thereof, which are useful as MGAT2inhibitors, including stereoisomers, tautomers, pharmaceuticallyacceptable salts, or solvates thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of multiple diseases or disorders associated with MGAT2,such as diabetes, obesity, dyslipidemia and related conditions, such asmicrovascular and macrovascular complications associated with diabetes,cardiovascular diseases, Metabolic Syndrome and its componentconditions, disorders of glucose and lipid metabolism and othermaladies.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment and/or prophylaxis of multiple diseases ordisorders associated with MGAT2.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present invention provides, inter alia, acompound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, wherein:

designates a single or double bond;

-   -   x and y can be both a single bond; when x is a double bond, then        y is a single bond and R⁴ and R¹⁶ are absent; when y is a double        bond, then x is a single bond and R⁵ and R¹⁶ are absent;    -   R¹ is independently selected from the group consisting of:        —CONH(C₄₋₁₈ alkyl), —CONHC₂₋₈ haloalkyl, —CONH(CH₂)₁₋₈Ph,        —CONHCH₂COC₂₋₈ alkyl, —(CH₂)_(m)—(C₃₋₁₀ carbocycle substituted        with 0-2 R^(b) and 0-2 R^(g)), —(CH₂)_(m)-(5- to 6-membered        heteroaryl comprising: carbon atoms and 1-4 heteroatoms selected        from N, NR^(e), O and S; wherein said heteroaryl is substituted        with 0-1 R^(b) and 0-2 R^(g)), and a C₁₋₁₂ hydrocarbon chain        substituted with 0-3 R^(a); wherein said hydrocarbon chain may        be straight or branched, saturated or unsaturated;    -   R² is independently selected from the group consisting of: C₁₋₄        alkyl, C₃₋₄ cycloalkyl, and C₁₋₄ haloalkyl;    -   R³ is independently selected from the group consisting of: H, F,        Cl, C₁₋₄ alkyl and CN;    -   R⁴ and R⁵ are independently selected from the group consisting        of: H, F, Cl, and C₁₋₄ alkyl;    -   when x is a single bond, R³ and R⁴ may be combined with the        carbon atom to which they are attached to form a 3- to        6-membered carbocycle;    -   R⁶ is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl, CN, NO₂, R^(c),        —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c), NH₂, —CONH(C₁₋₆ alkyl),        —NHCOX₁SO₂R^(j), —NHCOCH₂PO(OEt)₂, —NHCOCOR^(j),        —NHCOCH(OH)R^(j), —NHCOCH₂COR^(j), —NHCONHR^(j), and        —OCONR^(f)R^(j);    -   X is independently selected from the group consisting of: O, S,        NH, CONH, and NHCO;    -   X₁ is independently C₁₋₄ hydrocarbon chain optionally        substituted with C₁₋₄ alkyl or C₃₋₄ cycloalkyl;    -   when y is a single bond, R⁵ and R⁶ may be combined with the        carbon atom to which they are attached to form a 3- to        6-membered carbocycle;    -   R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are independently selected from the        group consisting of: H, halo, C₁₋₄ alkyl substituted with 0-2        R^(j), C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,        —(CH₂)_(m)—C₃₋₆ cycloalkyl, CN, NR^(f)R^(j), OR^(j), SR^(j),        NHCO₂(C₁₋₄ alkyl), NHSO₂(C₁₋₄ alkyl), and a 4- to 6-membered        heterocycle comprising: carbon atoms and 1-4 heteroatoms        selected from N, NR^(e), O, and S;    -   alternatively, R¹¹ and R¹², together with the carbon atoms to        which they are attached, combine to form a 5 to 6-membered        carbocyclic ring or a 5 to 6-membered heterocyclic ring        comprising: carbon atoms and 1-3 heteroatoms selected from N,        NR^(e), O, and S;    -   alternatively, R¹² and R¹³, together with the carbon atoms to        which they are attached, combine to form a 5 to 6-membered        carbocyclic ring or a 5 to 6-membered heterocyclic ring        comprising: carbon atoms and 1-3 heteroatoms selected from N,        NR^(e), O, and S;    -   R¹⁶ is independently selected from the group consisting of: H        and C₁₋₄ alkyl;    -   R^(a) is, at each occurrence, independently selected from the        group consisting of: halo, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆        haloalkoxy, N(C₁₋₄ alkyl)₂, —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c),        and —(CH₂)_(n)—(CH₂O)_(m)—(CH₂)_(n)R^(f);    -   R^(b) is, at each occurrence, independently selected from the        group consisting of: halo, OH, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀        haloalkyl, C₁₋₁₀ haloalkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀        haloalkylthio, N(C₁₋₄ alkyl)₂, —CONH(CH₂)₄₋₂₀H,        —O(CH₂)_(s)O(C₁₋₆ alkyl), R^(c),        —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c), and        —(CH₂)_(n)—(CH₂O)_(m)—CH₂)_(n)R^(f);    -   R^(c) is, at each occurrence, independently selected from the        group consisting of: C₃₋₆ cycloalkyl substituted with 0-2 R^(d),        C₃₋₆ cycloalkenyl substituted with 0-2 R^(d), —(CH₂)_(m)-(phenyl        substituted with 0-3 R^(d)), and a 5- to 6-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(e), O, and S; wherein said heterocycle is substituted with        0-2 R^(d);    -   R^(d) is, at each occurrence, independently selected from the        group consisting of: halo, OH, CN, NO₂, C₁₋₄ alkyl, C₁₋₄ alkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, tetrazolyl, OBn and phenyl        substituted with 0-2 R^(h);    -   R^(e) is, at each occurrence, independently selected from the        group consisting of: H, C₁₋₈ alkyl, C₁₋₈ haloalkyl, benzyl        optionally substituted with C₁₋₄ alkoxy, CO(C₁₋₄ alkyl) and        COBn;

R^(f) is, at each occurrence, independently selected from the groupconsisting of: H and C₁₋₄ alkyl;

R^(g), R^(h) and R^(i) are, at each occurrence, independently selectedfrom the group consisting of: halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy;

R^(j) is, at each occurrence, independently selected from the groupconsisting of: C₁₋₄ alkyl, C₃₋₄ cycloalkyl and phenyl;

-   -   n, at each occurrence, is independently 0 or 1;    -   m, at each occurrence, is independently 0, 1, 2, 3, or 4;    -   s, at each occurrence, is independently 1, 2, or 3; and    -   t, at each occurrence, is independently 0 or 1;    -   provided that the following compounds are excluded:

In a second aspect, the present invention includes a compound of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,or a solvate thereof, within the scope of the first aspect, wherein:

R¹ is independently selected from the group consisting of: —CONHC₄₋₁₈alkyl, —CONH(CH₂)₁₋₈ Ph, C₁₋₁₂ alkyl substituted with 0-2 R^(a), C₁₋₁₂alkenyl substituted with 0-2 R^(a), C₁₋₁₂ alkynyl substituted with 0-2R^(a), —(CH₂)_(m)-(phenyl substituted with 0-1 R^(b) and 0-2 R^(g)),—(CH₂)_(m)—(C₃₋₆ cycloalkyl substituted with 0-1 R^(b)), and—(CH₂)_(m)-(5- to 6-membered heteroaryl substituted with 0-1 R^(b) and0-2 R^(g)), wherein said heteroaryl is selected from: pyridyl, oxazolyl,thiazolyl and

In a third aspect, the present invention includes a compound of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,or a solvate thereof, within the scope of the first or second aspect,wherein:

-   -   R¹¹ and R¹⁵ are independently selected from the group consisting        of: H, C₁₋₄ alkyl and halo;    -   R¹² and R¹⁴ are independently selected from the group consisting        of: H, halo, C₁₋₄ alkyl and C₁₋₄ alkoxy; and    -   R¹³ is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl substituted with 0-1, R^(i), C₁₋₄ alkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkoxy, —(CH₂)_(m)—C₃₋₄ cycloalkyl, CN,        NR^(f)R^(j), SR^(j), NHCO₂(C₁₋₄ alkyl), NHSO₂(C₁₋₄ alkyl), and a        4- to 6-membered heterocycle comprising: carbon atoms and 1-4        heteroatoms selected from N, NR^(e), O, and S.

In a fourth aspect, the present invention provides a compound of Formula(II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof;

within the scope of any of the above aspects.

In a fifth aspect, the present invention includes a compound of Formula(I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of theabove aspects, wherein:

-   -   R¹ is independently selected from the group consisting of: C₁₋₆        alkyl, C₃₋₆ cycloalkyl, —CONHC₄₋₁₈ alkyl, —CONHC₂₋₈ haloalkyl,        —CONH(CH₂)₁₋₈ Ph, —(CH₂)_(m)-(phenyl substituted with 1 R^(b)        and 0-2 R^(g)), and a 5- to 6-membered heteroaryl substituted        with 0-1 R^(b) and 0-2 R^(g), wherein said heteroaryl is        selected from: pyridyl, oxazolyl, thiazolyl and

-   -   R² is independently selected from the group consisting of: C₁₋₄        alkyl and C₁₋₄ haloalkyl;    -   R³ is independently selected from the group consisting of: H and        F;    -   R⁴ is independently selected from the group consisting of: H and        F;    -   R⁶ is independently selected from the group consisting of: CN,        NH₂, —CONH(C₁₋₆ alkyl), R^(c),        —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c), —NHCO(CH₂)SO₂(C₁₋₄ alkyl),        —NHCOCH₂PO(OEt)₂, —NHCOCO(C₁₋₄ alkyl), —NHCOCH(OH)(C₁₋₄ alkyl),        —NHCOCH₂CO(C₁₋₄ alkyl), —NHCONH(C₁₋₄ alkyl), and —OCONH(C₁₋₄        alkyl);    -   R¹¹ and R¹⁵ are independently selected from the group consisting        of: H, C₁₋₄ alkyl and halo;    -   R¹² and R¹⁴ are independently selected from the group consisting        of: H, halo, C₁₋₄ alkyl and C₁₋₄ alkoxy;    -   R¹³ is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl substituted with 0-1 C₁₋₄ alkoxy, C₁₋₄ alkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, —(CH₂)_(m)—C₃₋₄ cycloalkyl, CN,        N(C₁₋₄ alkyl)₂, NHCO₂(C₁₋₄ alkyl), NHSO₂(C₁₋₄ alkyl), pyrazolyl,        and morpholinyl;    -   alternatively, R¹² and R¹³, together with the carbon atoms to        which they are attached, combine to form a 5 to 6-membered        carbocyclic ring or a 5 to 6-membered heterocyclic ring        comprising: carbon atoms and 1-3 heteroatoms selected from N,        NR^(e), O, and S;    -   R^(b) is, at each occurrence, independently selected from the        group consisting of: halo, OH, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈        haloalkyl, C₁₋₁₀ haloalkoxy, —O(CH₂)_(s)O(C₁₋₆ alkyl), N(C₁₋₄        alkyl)₂, —CONH(CH₂)₆₋₂₀H, —(CH₂)_(m)(C₃₋₆ cycloalkyl),        —(CH₂)_(m)(C₄₋₆ cycloalkenyl), —O(CH₂)_(m)(C₃₋₆ cycloalkyl),        4-C₁₋₄ alkoxy-Ph, —O(CH₂)_(1n)Ph, morpholinyl, pyridyl, 2-C₁₋₄        alkoxy-pyridin-5-yl, pyrimidinyl, pyrazinyl, and —O-pyrimidinyl;    -   R^(g) is, at each occurrence, independently selected from the        group consisting of: halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkyl, and C₁₋₄ haloalkoxy;    -   m, at each occurrence, is independently 0, 1, 2 or 3; and    -   s, at each occurrence, is independently 1, 2, or 3;    -   provided that the following compounds are excluded:

In a sixth aspect, the present invention includes a compound of Formula(I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of theabove aspects, wherein:

-   -   R¹ is independently selected from the group consisting of: C₁₋₆        alkyl, —CONHC₄₋₁₈ alkyl, —CONH(CH₂)₁₋₈Ph, and

-   -   R⁶ is independently selected from the group consisting of: CN,        NH₂, —CONH(C₁₋₆ alkyl), —NHCOCH₂PO(OEt)₂, —NHCO(CH₂)SO₂(C₁₋₄        alkyl), R^(c), OR^(c), —CONHR^(c), and —NHCOR^(c);    -   R¹² is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl and C₁₋₄ alkoxy;    -   R¹³ is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl substituted with 0-1 C₁₋₄ alkoxy, C₁₋₄ alkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, —(CH₂)_(m)—C₃₋₄ cycloalkyl, CN,        N(C₁₋₄ alkyl)₂, NHCO₂(C₁₋₄ alkyl), NHSO₂(C₁₋₄ alkyl), pyrazolyl,        and morpholinyl;    -   alternatively, R¹² and R¹³, together with the carbon atoms to        which they are attached, combine to form a 5 to 6-membered        carbocyclic ring or a 5 to 6-membered saturated heterocyclic        ring comprising: carbon atoms and 1-2 oxygen atoms;    -   R¹⁴ is independently selected from the group consisting of: H        and C₁₋₄ alkoxy;    -   R^(b) is, at each occurrence, independently selected from the        group consisting of: halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆        haloalkyl, C₁₋₁₀ haloalkoxy, —O(CH₂)_(s)O(C₁₋₆ alkyl),        —CONH(CH₂)₆₋₂₀H, —(CH₂)_(m)(C₃₋₆ cycloalkyl), —(CH₂)_(m)(C₄₋₆        cycloalkenyl), —O(CH₂)_(m)(C₃₋₆ cycloalkyl), phenoxy, benzoxy,        morpholinyl, 2-C₁₋₄ alkoxy-pyridin-5-yl, pyrimidin-5-yl,        pyrazin-2-yl and —O-pyrimidinyl; and    -   R^(c) is, at each occurrence, independently selected from the        group consisting of: C₃₋₆ cycloalkyl substituted with 0-2 R^(d),        —(CH₂)_(m)-(phenyl substituted with 0-3 R^(d)), and a heteroaryl        selected from: oxazolyl, isoxazolyl, thiazolyl, pyrazolyl,        imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, and        pyrazinyl; wherein said heteroaryl is substituted with 0-2        R^(d); and    -   provided that the following compounds are excluded:

In a seventh aspect, the present invention includes a compound ofFormula (I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of theabove aspects, wherein:

-   -   R¹ is

-   -   R⁶ is independently selected from the group consisting of: NH₂,        CN, —CONH(C₁₋₄ alkyl), OPh, —CONH(C₃₋₆ cycloalkyl), —CONHPh,        —CONH-(2-halo-Ph), —CONH-(3-halo-Ph), —CONH-(4-halo-Ph),        —CONH-(4-C₁₋₄ alkyl-Ph), —CONH(4-OH-Ph), —CONH-(3-C₁₋₄        alkoxy-Ph), —CONH-(4-C₁₋₄ alkoxy-Ph), —CONH-(4-C₁₋₄        haloalkyl-Ph), —CONH-(4-C₁₋₄ haloalkoxy-Ph), —CONH-(4-CN-Ph),        —CONH-(4-tetrazolyl-Ph), —CONH-(3-halo-4-C₁₋₄ alkyl-Ph),        —CONH-(3-halo-4-C₁₋₄ alkoxy-Ph), —CONH(CH₂)₂Ph, —CONH(4-(4-C₁₋₄        alkoxy-Ph)-thiazol-2-yl), —CONH(1-C₁₋₄ alkyl-pyrazol-3-yl),        —CONH(5-C₁₋₄ alkoxy-pyrid-2-yl), —CONH(6-C₁₋₄        alkoxy-pyrid-3-yl), —CONH(5-C₁₋₄ alkoxy-pyrazin-2-yl),        —CONH(6-C₁₋₄ alkoxy-pyridazin-3-yl), —NHCO(CH₂)SO₂(C₁₋₄ alkyl),        —NHCOPh, —NHCO(2-C₁₋₄ alkyl-Ph), —NHCO(3-C₁₋₄ alkyl-Ph),        —NHCO(4-C₁₋₄ alkyl-Ph), —NHCO(2-halo-Ph), —NHCO(3-halo-Ph),        —NHCO(2-C₁₋₄ haloalkyl-Ph), —NHCO(2-C₁₋₄ haloalkoxy-Ph),        —NHCO(2-halo-4-halo-Ph), —NHCO(2-halo-5-halo-Ph),        —NHCO(oxazolyl), —NHCO(isoxazolyl), —NHCO(3-C₁₋₄        alkyl-isoxazol-5-yl), —NHCO(4-C₁₋₄ alkyl-isoxazol-5-yl),        —NHCO(3-C₁₋₄ alkoxy-isoxazol-5-yl), —NHCO(4-C₁₋₄        alkoxy-isoxazol-5-yl), —NHCO(3-halo-isoxazol-5-yl),        —NHCO(3-OBn-isoxazol-5-yl), —NHCO(3-(2-halo-Ph)-isoxazol-5-yl),        —NHCO(3-(3-halo-Ph)-isoxazol-5-yl), —NHCO(5-C₁₋₄        alkyl-1H-pyrazol-3-yl), imidazolyl, —NHCO(5-C₁₋₄        alkyl-1,3,4-oxadiazol-2-yl), —NHCO(1-C₁₋₄        alkyl-1,2,3-triazol-4-yl), —NHCO(6-C₁₋₄ alkoxy-pyrid-3-yl),        —NHCO(pyrazinyl), —NHCO(6-halo-pyridazin-3-yl), 5-C₁₋₄        haloalkyl-1,3,4-oxadiazol-2-yl, 3-NO₂-1H-1,2,4-triazol-1-yl,        tetrazolyl and 5-C₁₋₄ alkyl-tetrazol-1-yl;    -   R^(b) is independently selected from the group consisting of:        halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₈ haloalkoxy,        —CONH(CH₂)₆₋₂₀H, C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl,        —O(CH₂)_(m)(C₃₋₆ cycloalkyl), phenoxy, benzoxy, pyrimidinyl,        pyrazinyl and —O-pyrimidinyl; and    -   R^(g) is independently selected from the group consisting of:        halo and C₁₋₄ alkyl;    -   provided that the following compounds are excluded:

In an eighth aspect, the present invention includes a compound ofFormula (I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of theabove aspects, wherein:

-   -   R² is independently selected from the group consisting of: CF₃        and Me;    -   R³ is independently selected from the group consisting of: H and        F;    -   R⁴ is independently selected from the group consisting of: H and        F;    -   R⁶ is independently selected from the group consisting of: NH₂,        CN, —CONHMe, OPh, —CONH(cyclopropyl), —CONH(cyclobutyl),        —CONH(cyclopentyl), —CONH(cyclohexyl), —CONHPh, —CONH(4-F-Ph),        —CONH(2-Cl-Ph), —CONH(4-Cl-Ph), —CONH(4-Me-Ph), —CONH(4-OH-Ph),        —CONH(3-OMe-Ph), —CONH(4-OMe-Ph), —CONH(4-CF₃-Ph),        —CONH(4-OCF₃-Ph), —CONH(1-Me-pyrazol-3-yl),        —CONH(4-(1H-tetrazol-2-yl)-Ph), —CONH(4-(2H-tetrazol-5-yl)-Ph),        —CONH(3-F-4-Me-Ph), —CONH(3-F-4-OMe-Ph), —CONH(CH₂)₂Ph,        —CONH(5-OMe-pyrid-2-yl), —CONH(6-OMe-pyrid-3-yl),        —CONH(5-OMe-pyrazin-2-yl), —CONH(6-OMe-pyridazin-3-yl),        —NHCO(CH₂)SO₂Me, —NHCOPh, —NHCO(2-Me-Ph), —NHCO(3-Me-Ph),        —NHCO(4-Me-Ph), —NHCO(2-Cl-Ph), —NHCO(3-Cl-Ph),        —NHCO(2-C₁₋₄—F-Ph), —NHCO(2-C₁₋₅—F-Ph), —NHCO(isoxazol-5-yl),        —NHCO(3-Me-isoxazol-5-yl), —NHCO(4-Me-isoxazol-5-yl),        —NHCO(3-OMe-isoxazol-5-yl), —NHCO(3-Br-isoxazol-5-yl),        —NHCO(3-(2-Cl-Ph)-isoxazol-5-yl),        —NHCO(3-(3-F-Ph)-isoxazol-5-yl), —NHCO(3-OBn-isoxazol-5-yl),        1H-imidazol-1-yl, —NHCO(5-Me-1,3,4-oxadiazol-2-yl),        —NHCO(1-Me-1,2,3-triazol-4-yl), —NHCO(6-OMe-pyrid-3-yl),        —NHCO(6-Cl-pyridazin-3-yl), 5-CF₃-1,3,4-oxadiazol-2-yl,        1H-tetrazol-1-yl, 1H-tetrazol-3-yl, and 2H-tetrazol-5-yl;    -   R¹¹ and R¹⁵ are independently selected from the group consisting        of: H, Me, F, and Cl;    -   R¹² is independently selected from the group consisting of: H,        F, Cl, Me and OMe;    -   R¹³ is independently selected from the group consisting of: H,        F, Cl, Br, Me, OMe, OEt, CH₂OMe, CF₃, CH₂CF₃, OCHF₂, OCF₃, CN,        N(Me)₂, cyclopropyl and cyclopropylmethyl;    -   alternatively, R¹² and R¹³, together with the carbon atoms to        which they are attached, combine to form a 5 to 6-membered        carbocyclic ring or a 5 to 6-membered saturated heterocyclic        ring comprising: carbon atoms and 1-2 oxygen atoms;    -   R¹⁴ is H;    -   R^(b) is, at each occurrence, independently selected from the        group consisting of: n-pentyl, methoxy, n-butoxy, i-butoxy,        i-pentoxy, —O(CH₂)₁₋₆CF₃, —O(CH₂)₁₋₄CF₂CF₃, —CONH(CH₂)₆₋₂₀H,        cyclopropyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl,        —O(CH₂)₂(cyclopentyl), phenoxy, benzoxy, pyrimidin-5-yl,        pyrazin-2-yl and —O-pyrimidin-2-yl; and    -   R^(g) is F;    -   provided that the following compound is excluded:

In a ninth aspect, the present invention includes a compound of Formula(I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of thefirst, second, third, fourth, fifth and sixth aspects, wherein:

-   -   R¹ is

-   -   R² is independently selected from CF₃ and CH₃;    -   R⁶ is independently selected from: CN, R^(c), —CONHR^(c),        —NHCOR^(c), and —NHCOCH₂SO₂ (C₁₋₄ alkyl);    -   R^(b) is independently selected from: —O(CH₂)₁₋₆CF₃,        —O(CH₂)₁₋₄CF₂CF₃, —CONH(CH₂)₆₋₂₀H, cyclopent-1-en-1-yl,        cyclohex-1-en-1-yl, —O(CH₂)₂(cyclopentyl), phenoxy, benzoxy,        pyrimidin-5-yl, pyrazin-2-yl and —O-pyrimidin-2-yl;    -   R^(c) is, at each occurrence, independently selected from the        group consisting of: —(CH₂)_(m)-(phenyl substituted with 0-3        R^(d)), and a heteroaryl selected from: oxazolyl, isoxazolyl,        pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl,        pyridyl, and pyrazinyl; wherein said heteroaryl is substituted        with 0-2 R^(d); and    -   R^(d) is, at each occurrence, independently selected from the        group consisting of: halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkoxy, tetrazolyl and OBn.

In another aspect, the present invention includes a compound of Formula(I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of thefirst, second, third, fourth, fifth, sixth and ninth aspects, wherein:

-   -   R¹ is

-   -   R² is independently selected from CF₃ and CH₃;    -   R⁶ is independently selected from: CN, R^(c), —CONHR^(c),        —NHCOR^(c), and —NHCOCH₂SO₂ (C_(1-zi) alkyl);    -   R¹¹, R¹², R¹⁴ and R¹⁵ are H;    -   R¹³ is independently selected from the group consisting of: H,        C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;        and    -   R^(b) is independently selected from: —O(CH₂)₁₋₆CF₃ and        —O(CH₂)₁₋₄CF₂CF₃.

In another aspect, the present invention includes a compound of Formula(II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,or a solvate thereof, within the scope of the fourth or fifth aspect,wherein:

-   -   R¹ is

-   -   R² is independently selected from CF₃ and CH₃;    -   R³ and R⁴ are H;    -   R⁶ is independently 5-membered nitrogen heteroaryl;    -   R¹¹, R¹², R¹⁴ and R¹⁵ are H;    -   R¹³ is independently selected from the group consisting of: H,        C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;        and    -   R^(b) is independently selected from: —O(CH₂)₁₋₆CF₃ and        —O(CH₂)₁₋₄CF₂CF₃.

In another aspect, the present invention includes a compound of Formula(II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,or a solvate thereof, within the scope of the fourth or fifth aspect,wherein:

-   -   R¹ is

-   -   R² is independently selected from CF₃ and CH₃;    -   R³ and R⁴ are H;    -   R⁶ is independently selected from: 1H-imidazol-1-yl,        1H-tetrazol-1-yl, 1H-tetrazol-3-yl, and 2H-tetrazol-5-yl;    -   R¹¹, R¹², R¹⁴ and R¹⁵ are H;    -   R¹³ is independently selected from the group consisting of: H,        Me, OMe, and OCHF₂; and    -   R^(b) is independently selected from: —O(CH₂)₁₋₆CF₃ and        —O(CH₂)₁₋₄CF₂CF₃.

In a tenth aspect, the present invention provides, inter alia, acompound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, wherein:

-   -   designates a single or double bond;    -   x and y can be both a single bond; when x is a double bond, then        y is a single bond and R⁴ and R¹⁶ are absent; when y is a double        bond, then x is a single bond and R⁵ and R¹⁶ are absent;    -   R¹ is independently selected from the group consisting of:        —(CH₂)_(m)—(C₃₋₁₀ carbocycle substituted with 0-3 R^(b)) or a        C₁₋₁₂ hydrocarbon chain substituted with 0-3 R^(a); wherein said        hydrocarbon chain may be straight or branched, saturated or        unsaturated;    -   R² is independently selected from the group consisting of: C₁₋₄        alkyl and C₁₋₄ haloalkyl;    -   R³ is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl and CN;    -   R⁴ and R⁵ are independently selected from the group consisting        of: H, halo and C₁₋₄ alkyl;    -   when x is a single bond, R³ and R⁴ may be combined with the        carbon atom to which they are attached to form a 3- to        6-membered carbocycle;    -   R⁶ is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl, CN, NO₂, and        —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c);    -   X is independently selected from the group consisting of: O, S,        NH, CONH and NHCO;    -   when y is a single bond, R⁵ and R⁶ may be combined with the        carbon atom to which they are attached to form a 3- to        6-membered carbocycle;    -   R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are independently selected from the        group consisting of: H, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkoxy, CN and a 5- to 6-membered        heterocycle comprising: carbon atoms and 1-4 heteroatoms        selected from N, NR^(e), O, and S;    -   R¹⁶ is independently selected from the group consisting of: H        and C₁₋₄ alkyl;    -   R^(a) is, at each occurrence, independently selected from the        group consisting of: halo, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆        haloalkoxy, N(C₁₋₄ alkyl)₂, —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c),        and —(CH₂)_(n)—(CH₂O)_(m)—(CH₂)_(n)R^(f);    -   R^(b) is, at each occurrence, independently selected from the        group consisting of: halo, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆        haloalkyl, C₁₋₆ haloalkoxy, —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c),        and —(CH₂)_(n)—(CH₂O)_(m)—(CH₂)_(n)R^(f);    -   R^(c) is independently selected from the group consisting of:        C₃₋₆ cycloalkyl substituted with 0-2 R^(d), phenyl substituted        with 0-3 R^(d), and a 5- to 6-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR^(e), 0, and        S; wherein said heterocycle is substituted with 0-2 R^(d);    -   R^(d) is, at each occurrence, independently selected from the        group consisting of: halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkyl, and C₁₋₄ haloalkoxy;    -   R^(e) is independently selected from the group consisting of: H,        C₁₋₄ alkyl, benzyl, CO(C₁₋₄ alkyl) and COBn;    -   R^(e) is independently selected from the group consisting of: H        and C₁₋₄ alkyl;    -   n, at each occurrence, is independently 0 or 1;    -   m, at each occurrence, is independently 0, 1, 2, 3 or 4; and    -   t, at each occurrence, is independently 0 or 1;    -   provided that the following compounds are excluded:

In an eleventh tenth aspect, the present invention includes a compoundof Formula (I), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of the tenthaspect, wherein:

-   -   R¹ is independently selected from the group consisting of: C₁₋₆        alkyl substituted with 0-2 R^(a), —(CH₂)_(m)-(phenyl substituted        with 0-3 R^(b)), and —(CH₂)_(m)—(C₃₋₆ cycloalkyl substituted        with 0-2 R^(b)).

In a twelfth aspect, the present invention includes a compound ofFormula (I), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of the tenth oreleventh aspect, wherein:

-   -   R¹¹ and R¹⁵ are independently selected from the group consisting        of: H and halo;    -   R¹² and R¹⁴ are independently selected from the group consisting        of: H, C₁₋₄ alkyl and C₁₋₄ alkoxy; and    -   R¹³ is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,        CN and morpholinyl.

In a thirteenth aspect, the present invention provides a compound ofFormula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof;within the scope of any of the tenth, eleventh and twelfth aspects.

In a fourteenth aspect, the present invention includes a compound ofFormula (I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of thetenth, eleventh, twelfth and thirteenth aspects, wherein:

-   -   R¹ is independently selected from the group consisting of: C₁₋₆        alkyl, C₃₋₆ cycloalkyl, —(CH₂)_(m)Ph and

-   -   R² is independently selected from the group consisting of: C₁₋₄        alkyl and C₁₋₄ haloalkyl;    -   R³ is H;    -   R⁴ is H;    -   R⁶ is independently selected from the group consisting of: CN,        NO₂, —CONH(C₁₋₆ alkyl), —CONHPh, —CONH-(3-halo-Ph),        —CONH-(4-halo-Ph), —CONH-(4-C₁₋₄ alkyl -Ph), —CONH-(3-C₁₋₄        alkoxy-Ph), —CONH-(4-C₁₋₄ alkoxy-Ph), —CONH-(4-C₁₋₄        haloalkyl-Ph), —CONH-(4-C₁₋₄ haloalkoxy-Ph),        —CONH-(3-halo-4-C₁₋₄ alkyl-Ph), —CONH-(3-halo-4-C₁₋₄ alkoxy-Ph),        —CONH(CH₂)₂Ph, and 2H-tetrazol-5-yl;    -   R¹¹ and R¹⁵ are independently selected from the group consisting        of: H and halo;    -   R¹² and R¹⁴ are independently selected from the group consisting        of: H, C₁₋₄ alkyl and C₁₋₄ alkoxy;    -   R¹³ is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,        CN and morpholinyl;    -   R^(b) is independently selected from the group consisting of:        halo, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆        haloalkoxy, —O(CH₂)_(m)O(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,        —O(CH₂)_(m)(C₃₋₆ cycloalkyl), 4-C₁₋₄ alkoxy-Ph, —O(CH₂)_(m)Ph,        pyridin-2-yl, 2-C₁₋₄ alkoxy-pyridin-5-yl, pyrimidin-5-yl,        pyrazin-2-yl and —O-pyrimidin-2-yl; and    -   m, at each occurrence, is independently 0, 1, 2 or 3.

In a fifteenth aspect, the present invention includes a compound ofFormula (I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of thetenth, eleventh, twelfth, thirteenth and fourteenth aspects, wherein:

-   -   R¹ is independently selected from the group consisting of: C₁₋₆        alkyl and

-   -   R⁶ is independently selected from the group consisting of: CN,        —CONH(C₁₋₆ alkyl), —CONHPh, —CONH-(3-halo-Ph),        —CONH-(4-halo-Ph), —CONH-(4-C₁₋₄ alkyl -Ph), —CONH-(3-C₁₋₄        alkoxy-Ph), —CONH-(4-C₁₋₄ alkoxy-Ph), —CONH-(4-C₁₋₄        haloalkyl-Ph), —CONH-(4-C₁₋₄ haloalkoxy-Ph),        —CONH-(3-halo-4-C₁₋₄ alkoxy-Ph), —CONH(CH₂)₂Ph, and        2H-tetrazol-5-yl;    -   R¹² is independently selected from the group consisting of: H,        C₁₋₄ alkyl and C₁₋₄ alkoxy;    -   R¹⁴ is independently selected from the group consisting of: H        and C₁₋₄ alkoxy;    -   R¹³ is independently selected from the group consisting of: H,        halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy        and CN;    -   R^(b) is independently selected from the group consisting of:        C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,        —O(CH₂)_(m)O(C₁₋₄ alkyl), —O(CH₂)_(m)(C₃₋₆ cycloalkyl), phenoxy,        benzoxy, 2-C₁₋₄ alkoxy-pyridin-5-yl, pyrimidin-5-yl,        pyrazin-2-yl and —O-pyrimidin-2-yl; and    -   m, at each occurrence, is independently 0, 1, 2 or 3;    -   provided that the following compounds are excluded:

In a sixteenth aspect, the present invention includes a compound ofFormula (I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of theninth, tenth, eleventh, twelfth, thirteenth, fourteenth and fifteenthaspects, wherein:

R¹ is

-   -   R⁶ is independently selected from the group consisting of: CN,        —CONHPh, —CONH-(4-halo-Ph), —CONH-(4-C₁₋₄ alkyl -Ph),        —CONH-(3-C₁₋₄ alkoxy-Ph), —CONH-(4-C₁₋₄ alkoxy-Ph),        —CONH-(4-C₁₋₄ haloalkyl-Ph), —CONH-(4-C₁₋₄ haloalkoxy-Ph),        —CONH-(3-halo-4-C₁₋₄ alkoxy-Ph), —CONH(CH₂)₂Ph, and        2H-tetrazol-5-yl; and    -   R^(b) is independently selected from the group consisting of:        C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,        —O(CH₂)_(m)(C₃₋₆ cycloalkyl), phenoxy, benzoxy, pyrimidin-5-yl,        pyrazin-2-yl and —O-pyrimidin-2-yl;    -   provided that the following compounds are excluded:

In a seventeenth aspect, the present invention includes a compound ofFormula (I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of theninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth andsixteenth aspects, wherein:

-   -   R² is independently selected from the group consisting of: CF₃        and Me;    -   R⁶ is independently selected from the group consisting of: CN,        —CONHPh, —CONH-(4-F-Ph), —CONH-(4-Cl-Ph), —CONH-(4-Me-Ph),        —CONH-(3-OMe-Ph), —CONH-(4-OMe-Ph), —CONH-(4-CF₃-Ph),        —CONH-(4-OCF₃-Ph), —CONH-(3-F-4-OMe-Ph), —CONH(CH₂)₂Ph, and        2H-tetrazol-5-yl;    -   R¹¹ and R¹⁵ are independently selected from the group consisting        of: H and F;    -   R¹² is independently selected from the group consisting of: H,        Me and OMe;    -   R¹³ is independently selected from the group consisting of: H,        F, Cl, Me, OMe, OEt, CF₃, OCHF₂, OCF₃ and CN;    -   R¹⁴ is H; and    -   R^(b) is independently selected from the group consisting of:        n-pentyl, methoxy, n-butoxy, i-butoxy, —O(CH₂)₁₋₃CF₃,        —O(CH₂)₂(cyclopentyl), phenoxy, benzoxy, pyrimidin-5-yl,        pyrazin-2-yl and —O-pyrimidin-2-yl;    -   provided that the following compounds are excluded:

In an eighteenth aspect, the present invention provides a compoundselected from the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds or a single compound from theexemplified examples within the scope of any of the above aspects.

In another aspect, the present disclosure provides a compound selectedfrom:

-   (S)-3-(1H-tetrazol-5-yl)-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one,-   (S)—N-(4-methoxyphenyl)-2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxamide,-   (S)-3-(2H-tetrazol-5-yl)-4-(p-tolyl)-6-(4-((6,6,6-trifluorohexyl)oxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one,-   (S)-2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile,-   (S)-2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-N-(4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxamide,-   (S)—N-(6-methoxypyridin-3-yl)-2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxamide,-   (S)—N-cyclopropyl-2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxamide,-   (S)—N-(4-hydroxyphenyl)-2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxamide,-   (S)-4-(4-(difluoromethoxy)phenyl)-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile,-   (S)-2-oxo-4-(p-tolyl)-6-(trifluoromethyl)-6-(4-(3,3,3-trifluoropropoxy)phenyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile,-   (S)-4-(4-(difluoromethoxy)phenyl)-3-(1H-tetrazol-1-yl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1R)-one,-   (S)-3-methyl-N-(2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridin-3-yl)isoxazole-5-carboxamide,-   (S)-5-methyl-N-(2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide,-   N²-heptyl-N⁵-(4-methoxyphenyl)-2-methyl-6-oxo-4-(p-tolyl)-1,2,3,6-tetrahydropyridine-2,5-dicarboxamide,-   (S)-3-(1H-tetrazol-1-yl)-4-(p-tolyl)-6-(4-(6,6,6-trifluorohexyl)oxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one,-   (S)-2-oxo-4-(p-tolyl)-6-(4-((6,6,6-trifluorohexyl)oxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile,-   (S)-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-3-(1H-tetrazol-5-yl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one,-   (S)-2-(methylsulfonyl)-N-(2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridin-3-yl)acetamide,-   (S)-3-(1H-tetrazol-5-yl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-4-(4-(2,2,2-trifluoroethyl)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one,    and-   (S)—N-(5-methoxypyrazin-2-yl)-2-oxo-4-(p-tolyl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxamide;    or a pharmaceutically acceptable salt thereof.

In another embodiment, R¹ is independently —CONH(C₄₋₁₈ alkyl), —CONHC₂₋₈haloalkyl, or —CONH(CH₂)₁₋₈Ph.

In another embodiment, R¹ is —(CH₂)_(m)—(C₃₋₁₀ carbocycle substitutedwith 0-2 R^(b) and 0-2 R^(g)), or —(CH₂)_(m)-(5- to 6-memberedheteroaryl comprising: carbon atoms and 1-4 heteroatoms selected from N,NR^(e), O and S; wherein said heteroaryl is substituted with 0-1 R^(b)and 0-2 R^(g)).

In another embodiment, R¹ is —(CH₂)_(m)—(C₃₋₁₀ carbocycle substitutedwith 0-2 R^(b) and 0-2 R^(g)).

In another embodiment, R¹ is —(CH₂)_(m)-(phenyl substituted with 0-2R^(b) and 0-2 R^(g)).

In another embodiment, R¹ is —(CH₂)_(m)-(5- to 6-membered heteroarylcomprising: carbon atoms and 1-4 heteroatoms selected from N, NR^(e), Oand S; wherein said heteroaryl is substituted with 0-1 R^(b) and 0-2R^(g)).

In another embodiment, R¹ is a C₁₋₁₂ hydrocarbon chain substituted with0-3 R^(a); wherein said hydrocarbon chain may be straight or branched,saturated or unsaturated.

In another embodiment, R¹ is independently: C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—CONHC₄₋₁₈ alkyl, —CONHC₂₋₈ haloalkyl, —CONH(CH₂)₁₋₈ Ph,—(CH₂)_(m)-(phenyl substituted with 1 R^(b) and 0-2 R^(g)), or a 5- to6-membered heteroaryl substituted with 0-1 R^(b) and 0-2 R^(g), whereinsaid heteroaryl is selected from: pyridyl, oxazolyl, thiazolyl and

In another embodiment, R¹ is independently: C₁₋₆ alkyl, —CONHC₄₋₁₈alkyl, —CONH(CH₂)₁₋₈Ph, or

In another embodiment, R¹ is

In another embodiment, R¹ is independently

In another embodiment, R² is independently C₁₋₄ alkyl or C₁₋₄ haloalkyl.

In another embodiment, R² is C₁₋₄ alkyl.

In another embodiment, R² is C₁₋₄ haloalkyl.

In another embodiment, R² is independently CF₃ or Me.

In another embodiment, R² is CF₃.

In another embodiment, R² is Me.

In another embodiment, R³ is independently H or F.

In another embodiment, R³ is H.

In another embodiment, R³ is F.

In another embodiment, R⁴ is independently H or F.

In another embodiment, R⁴ is H.

In another embodiment, R⁴ is F.

In another embodiment, R⁵ is independently H or F.

In another embodiment, R⁵ is H.

In another embodiment, R⁵ is F.

In another embodiment, R⁶ is independently C₁₋₄ alkyl, CN, R^(c), or—(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c).

In another embodiment, R⁶ is independently —CONH(C₁₋₆ alkyl),—NHCOX₁SO₂R^(j), —NHCOCOR^(j), —NHCOCH(OH)R^(j), —NHCOCH₂COR^(j),—NHCONHR^(j), or —OCONR^(f)R^(j).

In another embodiment, R⁶ is independently CN, NH₂, —CONH(C₁₋₆ alkyl),R^(c), —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c), —NHCO(CH₂)SO₂(C₁₋₄ alkyl),—NHCOCO(C₁₋₄ alkyl), —NHCOCH(OH)(C₁₋₄ alkyl), —NHCOCH₂CO(C₁₋₄ alkyl),—NHCONH(C₁₋₄ alkyl), or —OCONH(C₁₋₄ alkyl).

In another embodiment, R⁶ is independently CN, NH₂, —CONH(C₁₋₆ alkyl),—NHCO(CH₂)SO₂(C₁₋₄ alkyl), R^(c), OR^(c), —CONHR^(c), or —NHCOR^(c).

In another embodiment, R⁶ is independently CN, NH₂, —CONH(C₁₋₆ alkyl),—NHCO(CH₂)SO₂(C₁₋₄ alkyl), R^(c), OR^(c), —CONHR^(c), or —NHCOR^(c).

In another embodiment, R⁶ is independently CN, R^(c), —CONHR^(c),—NHCOR^(c), or —NHCOCH₂SO₂ (C₁₋₄ alkyl).

In another embodiment, R⁶ is independently 5-membered nitrogenheteroaryl.

In another embodiment, R⁶ is independently: 1H-imidazol-1-yl,1H-tetrazol-1-yl, 1H-tetrazol-3-yl, or 2H-tetrazol-5-yl.

In another embodiment, R¹¹ is independently H, C₁₋₄ alkyl or halo.

In another embodiment, R¹¹ is independently H, Me, F, or Cl.

In another embodiment, R¹¹ is H.

In another embodiment, R¹¹ is C₁₋₄ alkyl.

In another embodiment, R¹¹ is Me.

In another embodiment, R¹¹ is halo.

In another embodiment, R¹¹ is independently F or Cl.

In another embodiment, R¹² is independently H, halo, C₁₋₄ alkyl or C₁₋₄alkoxy.

In another embodiment, R¹² is independently H, F, Cl, Me and OMe.

In another embodiment, R¹² is H.

In another embodiment, R¹² is C₁₋₄ alkyl.

In another embodiment, R¹² is Me.

In another embodiment, R¹² is C₁₋₄ alkoxy.

In another embodiment, R¹² is OMe.

In another embodiment, R¹² is halo.

In another embodiment, R¹² is independently F or Cl.

In another embodiment, R¹³ is independently: H, halo, C₁₋₄ alkylsubstituted with 0-1 R^(i), C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₃₋₄ cycloalkyl, CN, NR^(f)R^(j), SR^(j), NHCO₂(C₁₋₄ alkyl),NHSO₂(C₁₋₄ alkyl), or a 4- to 6-membered heterocycle comprising: carbonatoms and 1-4 heteroatoms selected from N, NR^(e), O, and S.

In another embodiment, R¹³ is independently: H, halo, C₁₋₄ alkylsubstituted with 0-1 C₁₋₄ alkoxy, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, C₃₋₄ cycloalkyl, N(C₁₋₄ alkyl)₂, NHCO₂(C₁₋₄ alkyl),NHSO₂(C₁₋₄ alkyl), pyrazolyl, or morpholinyl.

In another embodiment, R¹³ is independently: H, halo, C₁₋₄ alkylsubstituted with 0-1 C₁₋₄ alkoxy, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN or C₃₋₄ cycloalkyl.

In another embodiment, R¹³ is independently: NR^(f)R^(j), NHCO₂(C₁₋₄alkyl), NHSO₂(C₁₋₄ alkyl), or a 4- to 6-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, NR^(e), O, and S.

In another embodiment, R¹⁴ is independently H, halo, C₁₋₄ alkyl or C₁₋₄alkoxy.

In another embodiment, R¹⁴ is independently H, F, Cl, Me and OMe.

In another embodiment, R¹⁴ is H.

In another embodiment, R¹⁴ is C₁₋₄ alkyl.

In another embodiment, R¹⁴ is Me.

In another embodiment, R¹⁴ is C₁₋₄ alkoxy.

In another embodiment, R¹⁴ is OMe.

In another embodiment, R¹⁴ is halo.

In another embodiment, R¹⁴ is independently F or Cl.

In another embodiment, R¹⁵ is independently H, C₁₋₄ alkyl or halo.

In another embodiment, R¹⁵ is independently H, Me, F, or Cl.

In another embodiment, R¹⁵ is H.

In another embodiment, R¹⁵ is C₁₋₄ alkyl.

In another embodiment, R¹⁵ is Me.

In another embodiment, R¹⁵ is halo.

In another embodiment, R¹⁵ is independently F or Cl.

In another embodiment, R¹⁶ is H.

In another embodiment, R¹⁶ is C₁₋₄ alkyl.

In another embodiment, X is independently O, S, or NH.

In another embodiment, X is independently O or S.

In another embodiment, X is O.

In another embodiment, X is independently CONH or NHCO.

In another embodiment, X is CONH.

In another embodiment, X is NHCO.

In another embodiment, R^(b) is, at each occurrence, independently:C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ haloalkyl, C₁₋₁₀ haloalkoxy, C₁₋₁₀alkylthio, C₁₋₁₀ haloalkylthio, —CONH(CH₂)₄₋₂₀H, —O(CH₂)_(s)O(C₁₋₆alkyl), R^(c), —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c), or—(CH₂)_(n)—(CH₂O)_(m)—(CH₂)_(n)R^(f).

In another embodiment, R^(b) is, at each occurrence, independently:halo, OH, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₁₋₁₀ haloalkoxy,—O(CH₂)_(s)O(C₁₋₆ alkyl), N(C₁₋₄ alkyl)₂, —CONH(CH₂)₆₋₂₀H,—(CH₂)_(m)(C₃₋₆ cycloalkyl), —(CH₂)_(m)(C₄₋₆ cycloalkenyl),—O(CH₂)_(m)(C₃₋₆ cycloalkyl), 4-C₁₋₄ alkoxy-Ph, —O(CH₂)_(m)Ph,morpholinyl, pyridyl, 2-C₁₋₄ alkoxy-pyridin-5-yl, pyrimidinyl,pyrazinyl, or —O-pyrimidinyl.

In another embodiment, R^(b) is, at each occurrence, independently:halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₁₀ haloalkoxy,—O(CH₂)_(s)O(C₁₋₆ alkyl), —CONH(CH₂)₆₋₂₀H, —(CH₂)_(m)(C₃₋₆ cycloalkyl),—(CH₂)_(m)(C₄₋₆ cycloalkenyl), —O(CH₂)_(m)(C₃₋₆ cycloalkyl), phenoxy,benzoxy, morpholinyl, 2-C₁₋₄ alkoxy-pyridin-5-yl, pyrimidin-5-yl,pyrazin-2-yl or —O-pyrimidinyl.

In another embodiment, R^(b) is, at each occurrence, independently:halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₈ haloalkoxy,—CONH(CH₂)₆₋₂₀H, C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl, —O(CH₂)_(m)(C₃₋₆cycloalkyl), phenoxy, benzoxy, pyrimidinyl, pyrazinyl and—O-pyrimidinyl.

In another embodiment, R^(b) is, at each occurrence, independently:—O(CH₂)₁₋₆CF₃ and —O(CH₂)₁₋₄CF₂CF₃.

In another embodiment, R^(c) is, at each occurrence, independently: C₃₋₆cycloalkyl substituted with 0-2 R^(d), C₃₋₆ cycloalkenyl substitutedwith 0-2 R^(d), or —(CH₂)_(m)-(phenyl substituted with 0-3 R^(d)).

In another embodiment, R^(c) is, at each occurrence, independently: C₃₋₆cycloalkyl substituted with 0-2 R^(d) or C₃₋₆ cycloalkenyl substitutedwith 0-2 R^(d).

In another embodiment, R^(c) is, at each occurrence, independently—(CH₂)_(m)-(phenyl substituted with 0-3 R^(d)).

In another embodiment, R^(c) is, at each occurrence, independently C₃₋₆cycloalkyl substituted with 0-2 R^(d).

In another embodiment, R^(c) is, at each occurrence, independently C₃₋₆cycloalkenyl substituted with 0-2 R^(d).

In another embodiment, R^(c) is, at each occurrence, independently a 5-to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NR^(e), O, and S; wherein said heterocycle issubstituted with 0-2 R^(d).

In another embodiment, R^(c) is, at each occurrence, independently—(CH₂)_(m)-(phenyl substituted with 0-3 R^(d)), or a heteroaryl selectedfrom: oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, oxadiazolyl,triazolyl, tetrazolyl, pyridyl, and pyrazinyl; wherein said heteroarylis substituted with 0-2 R^(d).

In another embodiment, R^(c) is, at each occurrence, independently aheteroaryl selected from: oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,oxadiazolyl, triazolyl, tetrazolyl, pyridyl, and pyrazinyl; wherein saidheteroaryl is substituted with 0-2 R^(d).

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤10 μM, using the MGAT2 SPA assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤5 μM, using the MGAT2 SPA assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤1 μM, using the MGAT2 SPA assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤0.5 μM, using the MGAT2 SPA assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤10 μM, using the MGAT2 LCMS assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤5 μM, using the MGAT2 LCMS assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤2.5 μM, using the MGAT2 LCMS assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤1 μM, using the MGAT2 LCMS assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤0.5 μM, using the MGAT2 LCMS assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values ≤0.1 μM, using the MGAT2 LCMS assay.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides an inte mediatefor making a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s). In apreferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent is, for example, adipeptidyl peptidase-IV (DPP4) inhibitor (for example a member selectedfrom saxagliptin, sitagliptin, vildagliptin and alogliptin).

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with MGAT2, comprising administering to a patient in need ofsuch treatment and/or prophylaxis a therapeutically effective amount ofat least one of the compounds of the present invention, alone, or,optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

Examples of diseases or disorders associated with the activity of theMGAT2 that can be prevented, modulated, or treated according to thepresent invention include, but are not limited to, diabetes,hyperglycemia, impaired glucose tolerance, gestational diabetes, insulinresistance, hyperinsulinemia, nonalcoholic fatty liver disease (NAFLD)including nonalcoholic steatohepatitis (NASH), retinopathy, neuropathy,nephropathy, delayed wound healing, atherosclerosis and its sequelae,abnormal heart function, myocardial ischemia, stroke, MetabolicSyndrome, hypertension, obesity, dyslipidemia, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, lowhigh-density lipoprotein (HDL), high low-density lipoprotein (LDL),non-cardiac ischemia, lipid disorders, and glaucoma.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of diabetes, hyperglycemia, gestationaldiabetes, obesity, dyslipidemia, and hypertension, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of diabetes, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of hyperglycemia, comprising administeringto a patient in need of such treatment and/or prophylaxis atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of obesity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of dyslipidemia, comprising administeringto a patient in need of such treatment and/or prophylaxis atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of hypertension, comprising administeringto a patient in need of such treatment and/or prophylaxis atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment and/orprophylaxis of multiple diseases or disorders associated with MGAT2.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment and/or prophylaxis of multiple diseases or disordersassociated with MGAT2.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with MGAT2, comprising: administering to a patient in needthereof a therapeutically effective amount of a first and secondtherapeutic agent, wherein the first therapeutic agent is a compound ofthe present invention. Preferably, the second therapeutic agent, forexample, dipeptidyl peptidase-IV (DPP4) inhibitor (for example a memberselected from saxagliptin, sitagliptin, vildagliptin, linagliptin andalogliptin).

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment and/or prophylaxis of multiple diseases or disordersassociated with MGAT2.

Where desired, the compound of the present invention may be used incombination with one or more other types of antidiabetic agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of antidiabetic agent that may be optionallyemployed in combination with the MGAT2 inhibitor of the presentinvention may be one, two, three or more antidiabetic agents orantihyperglycemic agents which may be administered orally in the samedosage form, in a separate oral dosage form, or by injection to producean additional pharmacological benefit.

The antidiabetic agents used in the combination with the MGAT2 inhibitorof the present invention include, but are not limited to, insulinsecretagogues or insulin sensitizers, other MGAT2 inhibitors, or otherantidiabetic agents. These agents include, but are not limited to,dipeptidyl peptidase IV (DP4) inhibitors (for example, sitagliptin,saxagliptin, alogliptin, linagliptin and vildagliptin), biguanides (forexample, metformin and phenformin), sulfonyl ureas (for example,glyburide, glimepiride and glipizide), glucosidase inhibitors (forexample, acarbose, miglitol), PPARγ agonists such as thiazolidinediones(for example, rosiglitazone and pioglitazone), PPAR α/γ dual agonists(for example, muraglitazar, tesaglitazar and aleglitazar), glucokinaseactivators, GPR40 receptor modulators (e.g. TAK-875), GPR119 receptormodulators (for example, MBX-2952, PSN821, and APD597), sodium-glucosetransporter-2 (SGLT2) inhibitors (for example, dapagliflozin,canagliflozin and remagliflozin), 11b-HSD-1 inhibitors (for exampleMK-0736, BI35585, BMS-823778, and LY2523199), amylin analogs such aspramlintide, and/or insulin.

The MGAT2 inhibitor of the present invention may also be optionallyemployed in combination with one or more hypophagic and/or weight-lossagents such as diethylpropion, phendimetrazine, phentermine, orlistat,sibutramine, lorcaserin, pramlintide, topiramate, MCHR1 receptorantagonists, oxyntomodulin, naltrexone, Amylin peptide, NPY Y5 receptormodulators, NPY Y2 receptor modulators, NPY Y4 receptor modulators,cetilistat, 5HT2c receptor modulators, and the like. The compounds ofthe present invention may also be employed in combination with anagonist of the glucagon-like peptide-1 receptor (GLP-1 R), such asexenatide, liraglutide, GPR-1(1-36) amide, GLP-1(7-36) amide,GLP-1(7-37), which may be administered via injection, intranasal, or bytransdermal or buccal devices.

The MGAT2 inhibitor of the present invention may also be optionallyemployed in combination with one or more other types of therapeuticagents, such as DGAT inhibitors, LDL lowering drugs such as statins(inhibitors of HMG CoA reductase) or inhibitors of cholesterolabsorption, modulators of PCSK9, drugs that increase HDL such as CETPinhibitors.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsounderstood that each individual element of the embodiments is its ownindependent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic fonds.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and inteiniediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free foini and salts thereof, may exist in multipletautomeric forms, in which hydrogen atoms are transposed to other partsof the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that alltautomeric forms, insofar as they may exist, are included within theinvention.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For examples, “C₁ to C₁₂alkyl” or “C₁₋₁₂ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ alkyl groups; “C₄ to C₁₈alkyl” or “C₄₋₁₈ alkyl” (or alkylene), is intended to include C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, and C₁₈ alkylgroups. Additionally, for example, “C₁ to C₆ alkyl” or “C₁₋₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl group can beunsubstituted or substituted with at least one hydrogen being replacedby another chemical group. Example alkyl groups include, but are notlimited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl), When “C₀ alkyl” or “C₀ alkylene” isused, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

When the term “hydrocarbon chain” is used, it is intended to include“alkyl”, “alkenyl” and “alkynyl”, unless otherwise specified.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. Forexample, “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intendedto include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), and t-butoxy. Similarly, “alkylthio” or“thioalkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample methyl-S— and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. For example, “C₃ to C₆ cycloalkyl” or“C₃₋₆ cycloalkyl” is intended to include C₃, C₄, C₅, and C₆ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”. Theterm “cycloalkenyl” refers to cyclized alkenyl groups. C₄₋₆ cycloalkenylis intended to include C₄, C₅, and C₆ cycloalkenyl groups. Examplecycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, and cyclohexenyl.

As used herein, “carbocycle,” “carbocyclyl,” or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic ring, any of which may be saturated, partially unsaturated,unsaturated or aromatic. Examples of such carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, itis intended to include “aryl.” A bridged ring occurs when one or more,preferably one to three, carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or bicyclic aromatic hydrocarbons,including, for example, phenyl, and naphthyl. Aryl moieties are wellknown and described, for example, in Hawley's Condensed ChemicalDictionary (15^(th) ed.), R. J. Lewis, ed., J. Wiley & Sons, Inc., NewYork, 2007. “C₆₋₁₀ aryl” refers to phenyl and naphthyl.

The term “benzyl,” as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle,” “heterocyclyl,” or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O) and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and Spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Examples of 5- to 6-membered heteroaryls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. and Greene, T. W. Protecting Groups in Organic Synthesis, 4thEdition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology,Vol. 3, Academic Press, New York (1981), the disclosure of which ishereby incorporated by reference. Examples of amine protecting groupsinclude, but are not limited to, the following: (1) acyl types such asformyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromaticcarbamate types such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are forming between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base foinis of these compoundswith a stoichiometric amount of the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington: TheScience and Practice of Pharmacy, 22^(nd) Edition, Allen, L. V. Jr.,Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   -   a) Bundgaard, H., ed., Design of Pro drugs, Elsevier (1985), and        Widder, K. et al., eds., Methods in Enzymology, 112:309-396,        Academic Press (1985);    -   b) Bundgaard, H., Chapter 5, “Design and Application of        Prodrugs,” A Textbook of Drug Design and Development, pp.        113-191, Krosgaard-Larsen, P. et al., eds., Harwood Academic        Publishers (1991);    -   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);    -   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);    -   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and    -   f) Rautio, J (Editor). Prodrugs and Targeted Delivery (Methods        and Principles in Medicinal Chemistry), Vol 47, Wiley-VCH, 2011.

Compounds containing a carboxy group can faun physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2^(nd) edition,reproduced, 2006); Testa, B. et al., Hydrolysis in Drug and ProdrugMetabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH,Zurich, Switzerland (2003); Wermuth, C. G., ed., The Practice ofMedicinal Chemistry, 3^(rd) edition, Academic Press, San Diego, Calif.(2008).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or min, “h” forhour or h, “rt” for room temperature, “RT” for retention time, “atm” foratmosphere, “psi” for pounds per square inch, “conc.” for concentrate,“aq” for “aqueous”, “sat” or “sat'd” for saturated, “MW” for molecularweight, “mp” for melting point, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC”or “tlc” for thin layer chromatography, “NMR” for nuclear magneticresonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, “Z” and “ee” arestereochemical designations familiar to one skilled in the art.

Me methyl Et ethyl Pr propyl i-Pr isopropyl Bu butyl i-Bu isobutyl t-Butert-butyl Ph phenyl Bn benzyl Hex hexanes MeOH methanol EtOH ethanoli-PrOH or IPA isopropanol AcOH or HOAc acetic acid Ag₂CO₃ silvercarbonate AgOAc silver acetate CDCl₃ deutero-chloroform CHCl₃ chloroformcDNA complimentary DNA DCC N,N′-dicyclohexylcarbodiimide DIADdiisopropyl azodicarboxylate DMA dimethylamine DME dimethylether DMFdimethyl formamide DMSO dimethyl sulfoxide DMAP 4-dimethylaminopyridineEDTA ethylenediaminetetraacetic acid EtOAc ethyl acetate Et₂O diethylether AlCl₃ aluminum chloride Boc tert-butyloxycarbonyl CH₂Cl₂dichloromethane CH₃CN or ACN acetonitrile Cs₂CO₃ cesium carbonate HClhydrochloric acid H₂SO₄ sulfuric acid K₂CO₃ potassium carbonate KCNpotassium cyanide mCPBA or m-CPBA meta-chloroperbenzoic acid Pd/Cpalladium on carbon PhSO₂Cl benzenesulfonyl chloride i-Pr₂NEtdiisopropylethylamine PS polystyrene SFC Supercritical FluidChromatography SiO₂ silica oxide SnCl₂ tin(II) chloride TBATtetrabutylammonium triphenydifluorosilicate TEA triethylamine TFAtrifluoroacetic acid THF tetrahydrofuran KOAc potassium acetate MgSO₄magnesium sulfate NaCl sodium chloride NaH sodium hydride NaHCO₃ sodiumbicarbonate NaOH sodium hydroxide Na₂SO₃ sodium sulfite Na₂SO₄ sodiumsulfate NH₃ ammonia NH₄Cl ammonium chloride NH₄OH ammonium hydroxide LGleaving group Pd₂dba₃ tris(dibenzylideneacetone)dipalladium(0)selectFluor N-fluoro-N′-methyl-triethylenediamine bis(tetrafluoroborate)

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transfottnationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Synthesis

The compounds of Formula (I) may be prepared by the exemplary processesdescribed in the following schemes and working examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working examples. Protection and de-protection inthe processes below may be carried out by procedures generally known inthe art (see, for example, Wuts, P. G. M. and Greene, T. W. ProtectingGroups in Organic Synthesis, 4th Edition, Wiley (2007)). General methodsof organic synthesis and functional group transformations are found in:Trost, B. M. and Fleming, I., eds., Comprehensive Organic Synthesis:Selectivity, Strategy & Efficiency in Modern Organic Chemistry, PergamonPress, New York, N.Y. (1991); Smith, M. B. and March, J., March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure. 6thEdition, Wiley & Sons, New York, N.Y. (2007); Katritzky, A. R. andTaylor, R. J. K., eds., Comprehensive Organic Functional GroupsTransformations II, 2nd Edition, Elsevier Science Inc., Tarrytown, N.Y.(2004); Larock, R. C., Comprehensive Organic Transformations, VCHPublishers, Inc., New York, N.Y. (1999), and references therein.

For example, compounds of Formula (II), where R³═R⁴═H and R⁶═CN, can bemade according to Scheme 1. Ketones 1 and 2 and 2-cyanoethyl acetate (3)are heated to between 80° C. and 110° C. with ammonium acetate in asolvent such as DMF or DMSO. Ketones 1 and 2 may be different or thesame.

Alternatively, compounds of Formula (II), where R³═R⁴═H, may be madeaccording to Scheme 2. α-Bromoketone 4 is combined withtriphenylphosphine in a solvent such as THF, CH₂Cl₂ or 1,4-dioxane attemperatures between room temperature and reflux. The intermediatetriphenylphosphonium bromide is treated with base, such as NaOH, in asolvent such as methanol and water to form the phosphorous ylide 5. Thephosphorous ylide 5 is heated to 80° C. with ketone 2 in a suitablesolvent such as THF or DMSO to give α,β-unsat'd ketone 6, which mayexist as a mixture of E/Z isomers. Microwave irradiation may be employedto shorten the reaction time. α,β-Unsat'd ketone 6 is treated withconcentrated aq NH₄OH in a solvent such as DMSO in a sealed vessel toprovide amine 7. Alternatively, alkene 6 may be treated with NH₃ in asolvent such as DMSO or DMSO and methanol in a sealed vessel to provideamine 7. Amine 7 is couple with carboxylic acid 8 using a variety ofamide bond forming reactions. For example, carboxylic acid 8 may beconverted to the corresponding acid chloride using oxalyl chloride in asolvent such as CH₂Cl₂ and catalytic DMF. Alternatively, when R⁶ is anamide or a heterocycle, the carboxylic acid 8 may be activated usingtriphenylphosphine and trichloroacetonitrile in a suitable solvent suchas CH₂Cl₂. The acid chlorides thus formed are combined with amine 7 in asuitable solvent such as CH₂Cl₂ or CH₂Cl₂ and DMF in the presence of abase, preferably pyridine. When R² is CF₃, cyclization of amide 9 to acompound of Formula (I) typically occurs during the work-up procedurefor amide 9; for example, when an EtOAc solution of amide 9 is washedwith sat'd aq NaHCO₃. When cyclization does not occur under theseconditions, cyclization may be affected by stirring amide 9 in thepresence of a weak base such as piperidine in a suitable solvent such asEtOH at a temperature between room temperature and reflux.

An alternate synthesis to α,β-unsaturated ketone 6, where R¹ is—(CH₂)_(m)— (phenyl substituted with 0-3 R^(b)) and m=0, is shown inScheme 3. Aryl bromide 10 and α,β-unsat'd ester 11 are coupled usingpalladium (II) acetate, tetrabutylammonium chloride anddicyclohexylamine in DMA at 110° C. α,β-Unsat'd ester 12 is combinedwith O,N-dimethylhydroxyl-amine 13 in the presence of a strong base suchas iso-propylmagnesium bromide in an aprotic solvent such as THF.α,β-Unsat'd amide 14 is combined with aryl magnesium halide 15 toprovide α,β-unsat'd ketone 6. The identity of the halide in the arylmagnesium halide is dependent upon availability of the aryl halide usedto make the Grignard reagent; typically the halide is chloride orbromide.

Non-commercial α,α□,α-trifluoroketones 2, where R²═CF₃, may be made fromthe corresponding aldehyde 16 as shown in Scheme 4. Aldehyde 16 isreacted with trimethyl-(trifluoromethyl)silane in the presence of afluoride source, for example cesium fluoride, using a suitable solventsuch dimethoxyethane at room temperature. Other fluoride sources, suchas potassium hydrogen fluoride or tetrabutylammoniumdifluorotriphenylsilicate, and other solvents, such as THF oracetonitrile and methanol, may also be employed. Trifluoromethyl alcohol17 is oxidized using, for example, Dess-Martin periodinane in a suitablesolvent such as CH₂Cl₂.

Ketones of formula 2 may be made according to Scheme 5. For example,aryl halide 18, where X=bromine and the aryl group is a suitablechemical moiety to form a Grignard reagent, is combined with magnesiummetal in the presence of an initiator such as iodine in a suitablesolvent such as THF. Other alkyl halides having a chemical moietysuitable for formation of Grignard reagents, other halides such aschlorine or iodine, other solvents such as diethyl ether or 1,4-dioxane,and other initiators such as 1,2-dibromoethene, may be employed asdetermined by one skilled in the art. Grignard reagent 19 is combinedwith amide 20 in a suitable solvent such as THF to provide ketone 2.Other solvents such as 1,4-dioxane or diethyl ether may be employed asdetermined by one skilled in the art.

Compounds of Formula 23 having R³═R⁴═H, R¹═—(CH₂)_(m)-(phenylsubstituted with 0-3 R^(b)) where m=0, and at least oneR^(b)═—(CH₂)_(n)—(X)_(r)(CH₂)_(m)—R^(c) where n=m=t=0, or n=m=0 and t=1when X=0 or NH, and R^(c) is a suitable chemical moiety to participatein palladium cross coupling reactions, may be made according to Scheme6. Compound 21 is heated with boronic acid 22, where R═H, in thepresence of a palladium catalyst and base using a suitable solvent suchas 1,4-dioxane, toluene, DMF with or without water. Boronic acid 22 maybe substituted with alternative boronic acid analogs such as boronateesters, trifluoroborates, and others known to those skilled in the art.Palladium catalyst commonly employed include, but are not restricted to,Pd(PPh₃)₄ and PdCl₂(dppf). Other palladium catalyst known to thoseskilled in the art may be employed. Bases commonly employed include, butare not restricted to, K₃PO₄ and K₂CO₃. Other bases known to thoseskilled in the art may also be employed. When n=m=0 and t=1 when X=0 orNH, biarylethers or biarylamines such as 23 can be obtained from 21 whenG=OH. Alternatively, biaryl ethers and amines can also be obtained from21, when G=boronic acid or equivalent, via metal-catalyzed coupling withsuitable phenols or amines

Compounds of Formula 27 having R³═R⁴═H, R¹═—(CH₂)_(m)-(phenylsubstituted with 0-3 R^(b)) where m=0, and at least oneR^(b)=—(CH₂)_(n)—(X)_(t)—(CH₂)_(m)—R^(c) where n=0, t=1, m=1-4 and X=0,may be made according to Scheme 7. Bromide 24 is treated withtris(dibenzylideneacetone)palladium (0) in the presence ofbis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine(t-butyl-Xphos) using 1,4-dioxane and water as solvent and KOH as base.Phenol 25 and alcohol 26 were stirred in the presence oftriphenylphosphine and DIAD in a suitable solvent such as CH₂Cl₂.

Carboxylic acid 8, where R⁶═CONHR^(c), may be made according to Scheme8. The mono-ester of malonic acid 28, where PG=benzyl group, and amine29 are coupled together using standard amide bond forming conditions.For example, treatment of carboxylic acid 28 with oxalyl chloride inCH₂Cl₂ and DMF provides the acid chloride. The acid chloride is thencombined with amine 29 in the presence of pyridine in a suitable solventsuch as CH₂Cl₂. Other amide bond forming reaction known to those skilledin the art may be employed. The benzyl group is removed using acombination of hydrogen gas and 10% palladium on carbon in a suitablesolvent such as methanol or methanol and EtOAc. Other PG moieties andmethods for their removal known to those skilled in the art may beemployed.

Compounds of Formula (I), where R³ and R⁴ are combined with the carbonatom to which they are attached to form a 3-6 membered carbocycle, orR³═R⁴═F, may be made according to Scheme 9. For example, to synthesizecompounds for Formula (I) where R³ and R⁴ are combined with the carbonatom to which they are attached to form a 3-membered ring (i.e.,cyclopropyl), β-ketoester 30 is stirred at room temperature with1,2-dibromoethane in the presence of a base, for example K₂CO₃, in asuitable solvent such as DMF to provide the cyclopropyl β-ketoester 31.Cyclopropyl β-ketoester 31 is stirred with a suitable amine, such asbenzyl amine, in the presence of a suitable Lewis acid, such as TiCl₄,in a solvent such as CH₂Cl₂ starting at 0° C. then warming to roomtemperature. Other amines, Lewis acids, solvents and temperatures may beused as determined by those skilled in the art. The use of benzylamineprovides imine 32, where PG=benzyl Imine 32 is alkylated with, forexample, trimethyl(trifluoromethyl)silane in the presence of a fluoridesource such as potassium hydrogen fluoride and TFA, using acetonitrileand DMF. Other fluoride sources, such as tetrabutylammoniumdifluorotriphenylsilicate or cesium fluoride, other acids such as HOAcor HCl, and other solvents may be employed as determined by thoseskilled in the art. Use of trimethyl(trifluoromethyl)silane providesamino ester 33, where R²═CF₃. Ester hydrolysis of amino ester 33 wasdone in the presence of lithium iodide in refluxing pyridine to provideamino acid 34. Use of other hydrolysis conditions known to those skilledin the art may be employed. Cyclization of amino acid 34 to β-lactam 35was affected by activating the carboxylic acid of amino acid 34 withoxalyl chloride in a suitable solvent such as CH₂Cl₂ containingcatalytic DMF. The cyclization occurred spontaneously at roomtemperature to provide β-lactam 35. Other methods for activating thecarboxylic acid may be employed as determined by those skilled in theart. β-Lactam 35 is arylated using an organometallic reagent.Organometallic reagents may include, for example, Grignard reagents ororganolithium reagents, formed from a suitably substituted phenyl ringcontaining a halide atom able to react with either elemental magnesiumto form a Grignard reagent or with an alkyl lithium reagent to form anphenyl lithium reagent via transmetallation. Exact conditions requiredto form these phenyl organometallic species must determined by thoseskilled in the art. A suitable aprotic solvent is used, for example,THF. Other suitable solvents may be employed as determined by thoseskilled in the art. The reaction is carried out between room temperatureand reflux depending upon the identity of the organometallic reagentemployed and the substitution pattern on β-lactam 35. The β-amino ketone37 thus formed is deprotected using hydrogen gas and 10% palladium oncarbon in a suitable solvent such as methanol containing 4.4% formicacid to provide β-amino ketone 38. Other conditions to remove the benzylgroup may be employed as determined by those skilled in the art. β-Aminoketone 38 is acylated with carboxylic acid 8 using conditions describedin Scheme 2 to give the β-keto amide 39. Stirring β-keto amide 39 with abase such as sodium ethoxide in a suitable solvent such as ethanol atroom temperature provides compounds having Formula (I).

Compounds of Formula (I), where y is a single bond and R⁵═F may be madeaccording to Scheme 10. This synthesis is exemplified for a compound ofFormula (I) where R⁶═CN. Thus, a compound of Formula (I), where x is asingle bond and R⁶═CN, was heated to 80° C. in the presence of afluorinating reagent,1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octanebis(tetrafluoroborate), in a suitable solvent such as DMF in thepresence of a base such as Na₂CO₃ to provide compounds of Formula (I),where y is a single bond, R⁵═F and R⁶═CN. Other fluorinating reagents,solvents and bases may be employed as determined by one skilled in theart.

Compounds of Formula (I), where x and y are both single bonds and R⁵═H,can be made according to Scheme 11. Reduction of compounds of Formula(I), where x equals a single bond and y equals a double bond, is carriedout using a suitable catalyst such as palladium on carbon under anatmosphere of hydrogen gas at suitable pressure, such as 50 psi, toeffect reduction of the double bond y to a single bond. Suitablesolvents include, but are not restricted to, methanol.

Compounds of Formula (II), single enantiomer, where R³═R⁴═H, can be madeaccording to Scheme 12. Ketone 2 was stirred with2-methylpropane-2-sulfinamide in the presence of a suitable Lewis acid,such as Ti(OEt)₄, in a solvent such as THF at refluxed temperatureprovides imine 40. Other Lewis acids, solvents and temperatures may beused as determined by those skilled in the art Imine 40 is alkylatedwith ketone 1 in the presence of a base, such as LiHMDS, KHMDS, NaHMDS,or LDA in an aprotic solvent such as THF or ether at a temperatureranging from −78° C. to ambient to provide β-amino ketone 41 as amixture of two diastereomers, which can be separated by silica gelchromatography to give the desired isomer 42. Other metal enolates (suchas titanium enolate), solvents, and temperatures may be used asdetermined by those skilled in the art (T. P. Tang, J. A Ellman, J. Org.Chem. 1999, 64, 12-13, J. Org. Chem. 2002, 67, 7819-7832). Preferably,chiral S- or R-2-methylpropane-2-sulfinamide can be optionally used togenerate each of the optically pure enantiomers of imine 40 that canallow for chiral induction to prepare diastereomerically enriched ketone42. In these cases, the product mixture can be further purified bysilica gel chromatography to obtain desired products with diasteromericexcess of >97%. β-amino ketone 42 thus formed is deprotected using HClin a suitable solvent such as MeOH to provide β-amino ketone 43. Otherconditions to remove the t-butylsulfinyl group may be employed asdetermined by those skilled in the art. β-Amino ketone 43 is acylatedwith carboxylic acid 8 using conditions described in Scheme 2 to givethe β-keto amide 44. Stirring β-keto amide 44 with a base such as sodiumethoxide in a suitable solvent such as ethanol at room temperatureprovides compounds having Formula (II).

Alternatively, compounds of Formula (II), where R³═R⁴═H, may be madeaccording to Scheme 13. Ketone 2 can be reacted with2-methylpropane-2-sulfinamide in the presence of a suitable Lewis acid,such as Ti(OEt)₄, in a solvent such as THF at a temperature ranging fromambient to reflux to provide imine 45. Other Lewis acids, solvents andtemperatures may be used as determined by those skilled in the art.Imine 45 is alkylated with the enolate of an ester in a suitable aproticsolvent such as THF or ether starting at −78° C. then warming to 0° C.or room temperature to provide protected β-amino ketone 46 as a mixtureof two diastereomers, which can be separated by silica gelchromatography to give each individual chiral compound. The generationof the ester enolate is achieved by treating the ester, such as methylacetate, with a suitable base such as LHMDS, KHMDS, NaHMDS, or LDA in anaprotic solvent such as THF or ether at a temperature ranging from −78°C. to ambient. Other metal enolates (such as titanium enolate),solvents, and temperatures may be used as determined by those skilled inthe art (T. P. Tang, J. A Ellman, J. Org. Chem. 1999, 64, 12-13, J. Org.Chem. 2002, 67, 7819-7832). Preferably, chiral S- orR-2-methylpropane-2-sulfinamide can be optionally used to generate eachof the optically pure enantiomers of imine 45 that can allow for chiralinduction to prepare diastereomerically enriched ester 46. In thesecases, the product mixture can be further purified by silica gelchromatography to obtain desired products with diaseteromeric excessof >97%. The tert-butyl sulfinyl group of 46 is removed using acids suchas HCl and TFA in a suitable solvent such as MeOH or dioxane to generateamino ester 47. Other conditions to remove the t-butylsulfinyl group maybe employed as determined by those skilled in the art. β-Amino ketone 47is acylated with carboxylic acid 8 using conditions described in Scheme2 to give the β-keto amide 48. Stirring β-keto amide 48 with a base suchas sodium ethoxide in a suitable solvent such as ethanol at roomtemperature to 80° C. provides cyclic enol 49. Other conditions can alsoby used to effect the cyclization as determined by those skilled in theart. Compound 49, when treated with stoichiometric amount of achlorinating agent, such as POCl₃, at elevated temperature in an inertsolvent such as toluene, is converted to mono-chloride 50. Chloride 50can then react with various boronic reagents through a Suzuki-type ofcross coupling reaction to generate compounds of Formula (II). Thechoices of boronic reagents, catalysts, ligands, bases, solvents andtemperatures are well documented in the literature and can be selectedappropriately by those skilled in the art.

Compounds of Formula (II), where R³═R⁴═H and R¹═CONHC₄₋₁₈ alkyl orCONH(CH₂)₁₋₈Ph can be made according to Scheme 14. The phosphorous ylide5 is heated, using microwave irradiation, to 150° C. with α-ketoester 52in a suitable solvent such as THF or DMSO to give α,β-unsat'd ketone 53.α,β-Unsat'd ketone 53 is treated with concentrated aq NH₄OH in a solventsuch as DMSO in a sealed vessel to provide amine 54. Alternatively,alkene 53 may be treated with NH₃ in a solvent such as DMSO or DMSO andmethanol in a sealed vessel to provide amine 54. Amine 54 is couple withcarboxylic acid 8 using a variety of amide bond forming reactions. Forexample, carboxylic acid 8 may be converted to the corresponding acidchloride using oxalyl chloride in a solvent such as CH₂Cl₂ and catalyticDMF. Alternatively, the carboxylic acid 8 may be activated using1-chloro-N,N,2-trimethylprop-en-1-amine in a suitable solvent such asCH₂Cl₂. The acid chlorides thus formed are combined with amine 54 in asuitable solvent such as CH₂Cl₂ or CH₂Cl₂ and DMF in the presence of abase, preferably pyridine. Other amide bond forming reaction known tothose skilled in the art may be employed. Cyclization of amide 55 andsubsequent hydrolysis to a the carboxylic acid 56 typically occurs bystirring amide 55 in the presence of a weak base such as piperidine in asuitable solvent such as EtOH at a temperature between room temperatureand reflux or a base such as lithium hydroxide in a suitable solventsuch as THF and water at room temperature. Alternatively, when R⁶ is anitrile, cyclization of amide 55 typically occurs by stirring amide 55in the presence of a base such as lithium hydroxide in a suitablesolvent such as THF and water at room temperature. Hydrolysis is thencarried out under acidic conditions using a strong acid such as HCl in asuitable solvent such as acetic acid at temperatures between roomtemperature and 50° C. Carboxylic acid 56 and an amine are coupledtogether using standard amide bond forming conditions. For example,treatment of carboxylic acid 56 and an amine with HOBt, EDC and DIEA inthe presence of pyridine in a suitable solvent such as DCM at roomtemperature provides compounds having Formula (II). Other amide bondforming reaction known to those skilled in the art may be employed.

Compounds of formula 60 having R^(e)=alkyl and R⁶=cyano can besynthesized by coupling acid 56 with N, O-dimethylhydroxylamine usingtypical amide bond forming reactions. For example, carboxylic acid 56 iscoupled to N, O-dimethylhydroxylamine using EDC in the presence of base,preferably N-methylmopholine, in a suitable solvent, such as CH₂Cl₂, toprovide the Weinreb amide 57. Other amide forming reactions known tothose skilled in the art may also be employed. The intermediate Weinrebamide 57 is reacted with ethynylmagnesium bromide in an aprotic solventsuch as THF at 0-35° C. to provide the acylacetylide intermediate 58.Compounds of formula 60 are obtained when acylacetylide intermediate 58is reacted with hydrazine 59 in the presence of a base such as TEA in asuitable solvent such as EtOH.

Compounds of formula 63 having R^(b)=alkyl and R⁶=cyano can besynthesized by first coupling acid 56 with β-ketoamine 61 using typicalamide bond forming reactions. For example, carboxylic acid 56 is coupledto α-ketoamine 61 using EDC and HOBt in the presence of base, preferablyDIEA, in a suitable solvent, such as CH₂Cl₂, to provide β-ketoamide 62.Other amide forming reactions known to those skilled in the art may alsobe employed. 5-Alkyl substituted oxazole 63 is then obtained via thedehydrative cyclization of β-ketoamide 62 using a dehydrating agent,preferably POCl₃, in the presence of a suitable base, such as DIEA, in asuitable solvent such as dichloroethane at a temperature of 80-120° C.

IV. Biology

In mammals, there are two triglyceride synthesis pathways:glycerol-3-phosphate pathway and monoacylglycerol pathway. The former ismainly responsible for energy storage in the peripheral tissues such asfat, liver, skeletal muscle; the latter is essential for the dietary fatabsorption which takes place in the small intestine. When dietary fat isingested, pancreatic lipase digests triglycerides into free fatty acidsand 2-monoacylglycerol, which are absorbed by intestinal epithelialenterocytes. Once inside enterocytes, free fatty acids and2-monoacylglycerol are used as building blocks to resynthesizetriglycerides by two sequential acylation steps; first by MGAT and thenby DGAT enzyme reactions. Triglycerides are then incorporated intochylomicrons and secreted into lymph to be utilized as an energy supplyfor the body.

Monoacylglycerol acyltransferase 2 (MGAT2) is a membrane boundacyltransferase that belongs to diacylglycerol acyltransferase 2 (DGAT2)gene family. It is highly and selectively expressed in the smallintestine. Genetic deletion of MGAT2 in mice decreased the rate ofabsorption for the orally ingested triglycerides, indicating that MGAT2plays an important role for the intestinal MGAT/DGAT pathway [Yen, C. L.et al, Nat. Med., 15(4):442-446 (2009); Okawa, M. et al., Biochem.Biophys. Res. Commun., 390(3):377-381 (2009)]. When chronicallychallenged with a high fat diet, in contrast to wild type mice thatbecame obese, MGAT2 knockout mice resisted the impact of high-fatfeeding and demonstrated with a lower body weight, less adiposity, andless hepatic fat accumulation. In contrast to hyperinsulinemic wild typemice after high-fat challenge, MGAT2 deletion normalizes the insulinlevel and decreased fasting glucose. In the glucose tolerance test, theyalso had an improved glucose excursion. Consistent with their improvedglycemic profile, MGAT2 knockout mice also had an increased level ofGLP1, an incretin gut hormone that profoundly impacts glucosemetabolism[Yen, C. L. et al., Nat. Med., 15(4):442-446 (2009)]. Takentogether, it is expected that inhibition of MGAT2 throughpharmacological intervention would provide the same benefit asdemonstrated in the knock-out mice, e.g., resistance to weight gain, orconversely, reduction in fat body mass. In addition, MGAT2 inhibitionwould lead to an improved insulin sensitivity and glucose metabolismwhich either leads to a decrease in the incidence of Type II diabetes,or a treatment of diabetic condition.

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known anti-diabetic agents,in one or more of the following categories that are given as examples,and are not intended to be limiting: (a) phainiacokinetic properties,including oral bioavailability, half life, and clearance; (b)phainiaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood drug concentration peak-to-trough characteristics; (e)factors that increase the concentration of active drug at the receptor;(f) factors that decrease the liability for clinical drug-druginteractions; (g) factors that decrease the potential for adverseside-effects, including selectivity versus other biological targets; and(h) improved therapeutic index with less propensity for hypoglycemia.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-humanorganism that could potentially benefit from treatment with a MGAT2inhibitor. Exemplary subjects include human beings of any age with riskfactors for metabolic disease. Common risk factors include, but are notlimited to, age, sex, weight, family history, or signs of insulinresistance such as acanthosis nigricans, hypertension, dyslipidemia, orpolycystic ovary syndrome (PCOS).

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit MGAT2 and/or to prevent or treat thedisorders listed herein. When applied to a combination, the term refersto combined amounts of the active ingredients that result in thepreventive or therapeutic effect, whether administered in combination,serially, or simultaneously.

A. Assay Methods

MGAT SPA Assay

MGAT2 enzyme was assayed using membranes isolated from Sf9 cellsexpressing the recombinant human MGAT2 cDNA with 2-monooleoylglyceroland [³H]-oleoyl-CoA as substrates as described by Seethala et al. [Anal.Biochem., 383(2):144-150 (Dec. 15, 2008)]. Briefly, the assays wereconducted in 384-well plates in a total volume of 30 μL at 25° C. Ineach assay, 200 ng of recombinant human MGAT2 membrane was incubatedwith 10 μM of 2-monooleoylglycerol and 15 μM of [³H]-oleoyl-CoA in 100mM potassium phosphate (pH 7.4) for 20 min with various concentrationsof compounds delivered in DMSO. The assay was terminated by the additionof 20 μl of Stopping Solution (7.5 mg/ml Yittrium Oxide Polylysinebeads, 3.3 mg/ml Fraction V BSA and 200 μM Mercuric chloride in 50 mMHEPES, pH 7.4). The signal was measured 1 h after quenching the reactionusing LEADSEEKER℠ for 5 minutes. To calculate the degree of inhibition,the zero level of enzyme activity (blank) was defined by the above assayprocedure using membrane form Sf9 cell uninfected with baculovirus(Naive) and the 100% level of MGAT2 enzyme activity was defined by humanMGAT2 assay with the vehicle DMSO. The IC₅₀s of inhibitors weredetermined by logistic 4 parameter equation in XL-fit.

MGAT LCMS Assay

The MGAT enzyme reactions were performed in CORNING Falcon 96-wellPolypropylene plates, in a total volume of 60 μL of 50 mM PotassiumPhosphate buffer pH 7.4, containing a final concentration of 100 μM2-oleoylglycerol, 15 μM oleoyl-Coenzyme A and 0.0013 μg/μL Human orMouse MGAT-2 or 0.0026 μg/μL Rat recombinant MGAT-2 membranes expressedin Sf9 cells. Assay plates were run through a fully automated roboticssystem and shaken for 5 seconds every minute for a total 10 minutes. Thereactions were then quenched with 120 μL of ice cold methanol containing1 μg/mL 1,2-distearoyl-rac-glycerol as the internal standard. Plateswere shaken for 2 minutes and spun down to remove protein precipitation.After the spin, samples were transferred to LC/MS compatible PCR plates.For LC/MS analysis, a ThermoFisher Surveyor pump, utilizing a WatersSymmetry C8, 50×2.1 mm column, was used for the chromatography of enzymeproducts. The buffer system consists of 0.1% formic acid in water with amobile phase consisting 0.1% formic acid in methanol. The shallowgradient is 90-100% mobile phase in 0.2 min with a total run time of 2.3min. The first 0.5 minutes of each injection was diverted to waste toeliminate the presence of Phosphate buffer in the enzymatic reaction.The column was run at 0.6 mL/min and a temperature of 65° C. Massspectrometry analysis of the samples was performed on a ThermoFisherQuantum Triple quad utilizing APCI (+) as the mode of ionization. Datawas acquired in Single Ion Monitoring (SIM) mode analyzing Diolein=m/z603.6 (PRODUCT) and 1,2-distearoyl-rac-glycerol (IS)=m/z 607.6. Theratio of Diolein to internal standard (Peak Area Ratio) is utilized tocalculate IC₅₀ values.

The exemplified Examples disclosed below were tested in the MGAT2 invitro assays described above and were found having MGAT2 inhibitoryactivity. Table 1 below lists human MGAT2 IC₅₀ values measured for thefollowing examples. “NT” denotes “Not tested”.

TABLE 1 Example h-MGAT2 IC₅₀ (nM) No. SPA Assay LCMS Assay 1 651 2049 285 5  2-1 35 8  2-2 1400 261 3 1804 NT 4 5871 NT 5 309 21 6 15 7  6-11435 NT  6-2 14 2 7 818 NT 8 NT 7 9 33330 121 10 2716 138 11 48 13 12 NT374 13 3333 35 14 NT 2050 15-1 3306 12 15-2 33330 431 15-3 33330 75615-4 33330 2049 16-1 25 7 16-2 8430 416 17 1931 NT 18 5762 NT 19 2905 NT20 3456 NT 21 913 NT 22 801 NT 23 1292 NT 24 1731 NT 25 4569 NT 26 6428NT 27 2519 NT 28 564 NT 29 7602 NT 30 774 NT 31 1510 NT 32 9956 NT 33167 12 34 656 126 35 5199 13 36 396 57 37 263 15 38 2143 NT 39 401 20 402546 164 41 170 15 42 403 77 43 5387 60 44 1458 NT 45 569 NT 46 871 NT47 756 NT 48 226 7 49 127 64 50 242 95 51 63 13 52 477 99 53 111 3 54258 20 55 846 20 56 6550 NA 57 412 16 58 275 29 59 53 4 60 441 12 61 709NT 62 156 24 63 116 28 64 761 280 65 96 3 66 731 265 67 1935 253 68 75231282 69 9230 983 70 3404 NA 71 2931 1917 72 3519 214 73 684 15 74 2476697 75 873 209 76 5073 370 77 89 27 78 151 4 79 1856 45 80 310 5 81 55 482 133 2 83 89 1 84 115 2 85 1465 7 86 201 1 87 NT 1215 88 28 5 89 73120 90 815 18 91 916 2 92 NT 136 93 37 30 94 32 4 95 95 43 96 NT 1431 97NT 1199 98 154 69 99 NT 795 100 NT 1575 101 379 108 102 NT 1088 103 NT645 104 NT 103 105 672 24 106 NT 552 107 NT 93 108 NT 189 109 NT 39 11011 5 111 9 7 112 1297 204 113 158 8 114 NT 704 115 NT 40 116 48 4 117 2218 118 32 4 119 94 21 120 58 6 121 231 20 122 14 1 123 743 5 124 4264 55125 NT 282 126 1874 33 127 655 10 128 NT 328 129 NT 222 130 20 1 131 NT1050 132 NT 163 133 1518 127 134 NT 168 135 NT 778 136 NT 328 137 NT 252138 NT 5799 140 NT 356 141 NT 459 142 93 10 143 156 4 144 175 16 145 13025 146 397 25 147 91 14 148 102 9 149 53 6 150 11 3 151 NT 5115 152 NT252 153 NT 247 154 34 8 155 NT 484 156 NT 254 157 168 84 158 302 75 159NT 16710 160 NT 5401 161 NT 1261 162 NT 214 163 1176 47 164 NT 162 16560 8 166 237 102 167 8 2 168 NT 113 169 NT 421 170 NT 210 171 724 57 17216 3 173 43 63 174 237 60 175 NT 264 176 NT 3 177 NT 399 178 47 78 17924 2 180 36 30 181 NT 2049 182 NT 2049 183 NT 50 184 NT 76 185 NT 121186 NT 229 187 NT 4 188 NT 1524 189 NT 1159 190 NT 155 191 NT 797 192 NT433 193 NT 46 194 NT 6 195 NT 33 196 NT 826 197 NT 178 198 NT 16 199 NT16 200 NT 37 201 NT 24 202 NT 89 203 NT 59 204 NT 41 205 NT 13 206 NT 78207 NT 11 208 NT 30 209 NT 37 210 NT 2 211 NT 97 212 NT 416 213 NT 1096214 NT 12 215 NT 11 216 NT 440 217 NT 118 218 NT 166 219 NT 172 220 NT13 221 NT 152 222 NT 733 223 NT 112 224 NT 414 225 NT 889 226 NT 206 227NT 63 228 NT 7 229 NT 25 230 NT 1532 231 NT 34 232 NT 6 233 NT 639 234NT 40 235 NT 22 236 NT 489 237 NT 130 238 NT 7 239 NT 15 240 NT 7 242 NT44 243 NT 14 244 NT 61 245 NT 46 246 NT 36 247 NT 51 248 NT 8 249 NT 185250 NT 243 251 NT 3 252 NT 7 253 NT 411 254 NT 170 255 NT 702 256 NT 22257 NT 421 258 NT 1147 259 NT 15 260 NT 56 261 NT 1222 262 NT 96 263 NT103 264 NT 46 265 NT 40 266 NT 10 267 NT 796 268 NT 8 269 NT 171 270 NT407 271 NT 12 272 NT 112 273 21 10 274 NT 1 275 NT 2 276 NT 2 277 NT 2278 NT 2 279 NT 2 280 NT 2 281 NT 3 282 NT 3 283 NT 3 284 NT 4 285 NT 4286 NT 4 287 NT 13 288 NT 19 289 NT 19 290 NT 56 291 NT 178 292 NT 304293 NT 7 294 NT 84 295 NT 183 296 NT 2 297 NT 639 298 NT 2 299 NT 11 300NT 11 301 NT 19 302 NT 105 303 NT 28 304 NT 6 305 NT 94 306 NT 3 307 NT3 308 NT 61 309 NT 1 310 NT 4 311 NT 3 312 NT 21 313 NT 4 314 NT 109

The compounds of the present invention possess activity as inhibitors ofMGAT2, and, therefore, may be used in the treatment of diseasesassociated with MGAT2 activity. Via modulation of MGAT2, the compoundsof the present invention may preferably be employed to modulate, eitherenhance or decrease the production/secretion of insulin and/or guthormones, such as GLP1, GIP, CCK, PYY, PP, Amylin.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of diabetes and relatedconditions, microvascular complications associated with diabetes,macrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, inflammatorydiseases and other maladies. Consequently, it is believed that thecompounds of the present invention may be used in preventing,inhibiting, or treating diabetes, hyperglycemia, impaired glucosetolerance, gestational diabetes, insulin resistance, hyperinsulinemia,retinopathy, neuropathy, nephropathy, wound healing, atherosclerosis andits sequelae (acute coronary syndrome, myocardial infarction, anginapectoris, peripheral vascular disease, intermittent claudication,myocardial ischemia, stroke, heart failure), Metabolic Syndrome,hypertension, obesity, dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, lipiddisorders, PCOS, and glaucoma.

Metabolic Syndrome or “Syndrome X” is described in Ford et al., J. Am.Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med.Chem.—Imm., Endoc. & Metab. Agents, 1:1-24 (2001).

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; bucally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, L. V. Jr. et al. Remington: The Science and Practiceof Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more other therapeutic agent(s), e.g., an antidiabetic agentor other pharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other MGAT2 inhibitors or one or more other suitable therapeuticagents useful in the treatment of the aforementioned disordersincluding: anti-diabetic agents, anti-hyperglycemic agents,anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathicagents, anti-nephropathic agents, anti-atherosclerotic agents,anti-ischemic agents, anti-hypertensive agents, anti-obesity agents,anti-dyslipidemic agents, anti-dyslipidemic agents, anti-hyperlipidemicagents, anti-hypertriglyceridemic agents, anti-hypercholesterolemicagents, anti-restenotic agents, anti-pancreatic agents, lipid loweringagents, anorectic agents, memory enhancing agents, anti-dementia agents,or cognition promoting agents, appetite suppressants, treatments forheart failure, treatments for peripheral arterial disease andanti-inflammatory agents.

Where desired, the compound of the present invention may be used incombination with one or more other types of antidiabetic agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of antidiabetic agent that may be optionallyemployed in combination with the MGAT2 inhibitor of the presentinvention may be one, two, three or more antidiabetic agents orantihyperglycemic agents which may be administered orally in the samedosage form, in a separate oral dosage form, or by injection to producean additional pharmacological benefit.

The antidiabetic agents used in the combination with the compound of thepresent invention include, but are not limited to, insulin secretagoguesor insulin sensitizers, other MGAT2 inhibitors, or other antidiabeticagents. These agents include, but are not limited to, dipeptidylpeptidase IV (DP4) inhibitors (for example, sitagliptin, saxagliptin,alogliptin, vildagliptin and the like), biguanides (for example,metformin, phenfoimin and the like), sulfonyl ureas (for example,glyburide, glimepiride, glipizide and the like), glucosidase inhibitors(for example, acarbose, miglitol, and the like), PPARγ agonists such asthiazolidinediones (for example, rosiglitazone, pioglitazone, and thelike), PPAR α/γ dual agonists (for example, muraglitazar, tesaglitazar,aleglitazar, and the like), glucokinase activators (as described inFyfe, M. C. T. et al., Drugs of the Future, 34(8):641-653 (2009) andincorporated herein by reference), GPR40 receptor modulators, GPR119receptor modulators (MBX-2952, PSN821, APD597 and the like), SGLT2inhibitors (dapagliflozin, canagliflozin, remagliflozin and the like),amylin analogs such as pramlintide, and/or insulin. Reviews of currentand emerging therapies for the treatment of diabetes can be found in:Mohler, M. L. et al., Medicinal Research Reviews, 29(1):125-195 (2009),and Mizuno, C. S. et al., Current Medicinal Chemistry, 15:61-74 (2008).

The compounds of the present invention may also be optionally employedin combination with agents for treating complication of diabetes. Theseagents include PKC inhibitors and/or AGE inhibitors.

The compounds of the present invention may also be optionally employedin combination with one or more hypophagic agents such asdiethylpropion, phendimetrazine, phentermine, orlistat, sibutramine,lorcaserin, pramlintide, topiramate, MCHR1 receptor antagonists,oxyntomodulin, naltrexone, Amylin peptide, NPY Y5 receptor modulators,NPY Y2 receptor modulators, NPY Y4 receptor modulators, cetilistat,5HT2c receptor modulators, and the like. The compound of structure I mayalso be employed in combination with an agonist of the glucagon-likepeptide-1 receptor (GLP-1 R), such as exenatide, liraglutide,GPR-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S.Pat. No. 5,614,492 to Habener, the disclosure of which is incorporatedherein by reference), which may be administered via injection,intranasal, or by transdermal or buccal devices. Reviews of current andemerging therapies for the treatment of obesity can be found in:Melnikova, I. et al., Nature Reviews Drug Discovery, 5:369-370 (2006);Jones, D., Nature Reviews: Drug Discovery, 8:833-834 (2009); Obici, S.,Endocrinology, 150(6):2512-2517 (2009); and Elangbam, C. S., Vet.Pathol., 46(1):10-24 (2009).

The compounds of the present invention may also be optionally employedin combination with one or more other types of therapeutic agents, suchas DGAT inhibitors, LDL lowering drugs such as statins (inhibitors ofHMG CoA reductase) or inhibitors of cholesterol absorption, modulatorsof PCSK9, drugs increase HDL such as CETP inhibitors.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate form's but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the MGAT2 enzyme. Such compounds may beprovided in a commercial kit, for example, for use in pharmaceuticalresearch involving MGAT2 or anti-diabetic activity. For example, acompound of the present invention could be used as a reference in anassay to compare its known activity to a compound with an unknownactivity. This would ensure the experimentor that the assay was beingperformed properly and provide a basis for comparison, especially if thetest compound was a derivative of the reference compound. Whendeveloping new assays or protocols, compounds according to the presentinvention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving MGAT2.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment and/or prophylaxis of multiple diseases ordisorders associated with MGAT2 (as defined previously). In anotherembodiment, the package insert states that the pharmaceuticalcomposition can be used in combination (as defined previously) with asecond therapeutic agent for the treatment and/or prophylaxis ofmultiple diseases or disorders associated with MGAT2. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

VI. Examples

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

HPLC/MS, Preparatory/Analytical HPLC, and Chiral Separation MethodsEmployed in Characterization or Purification of Examples

Analytical HPLC/MS (unless otherwise noted) was performed on ShimadzuSCL-10A liquid chromatographs and Waters MICROMASS® ZQ MassSpectrometers (Desolvation Gas: Nitrogen; Desolvation Temp. 250° C.; IonSource Temp: 120° C.; Positive Electrospray conditions) using thefollowing methods:

Linear Gradient of 0% to 100% solvent B over 2 min, with 1 minute holdat 100% B, or

Linear Gradient of 0% to 100% solvent B over 4 min, with 1 minute holdat 100% B;

UV visualization at 220 nm;

Column: PHENOMENEX® Luna C18 (2) 30 mm×4.6 mm; 5μ particle (heated toTemp. 40° C.);

Flow rate: 1.0 mL/min (2 min gradient) or 0.8 ml/min (4 min gradient);

Solvent A: 10% ACN, 90% water, 0.1% TFA; or, 10% MeOH, 90% water, 0.1%TFA and

Solvent B: 90% ACN, 10% water, 0.1% TFA; or, 90% MeOH, 10% water, 0.1%TFA.

Preparatory HPLC (unless otherwise noted) was performed on a ShimadzuSCL-10A liquid chromatograph with a linear gradient of 20-100% Solvent Bover 10 to 30 min, with either a 2 to 5 min hold at 100% Solvent B asdetermined by on skilled in the art;

UV visualization at 220 nm;

Column: PHENOMENEX® Luna Axia 5μ, C18 30×100 mm;

Flow rate: 20 mL/min;

Solvent A: 10% ACN, 90% water, 0.1% TFA; or 10% MeOH, 90% water, 0.1%TFA; and

Solvent B: 90% ACN, 10% water, 0.1% TFA; or 90% MeOH, 10% water, 0.1%TFA.

Preparatory chiral SFC chromatography (unless otherwise noted) wasperformed on a Berger Multigram II SFC chromatograph using one of thefollowing methods:

Preparative chiral SFC method A:

Column: CHIRALCEL® OD-H, 30×250 mm ID, 5μ

Flow rate: 90 mL/min, 100 bar BP, 40° C.

Mobile Phase: 15% Methanol/85% CO₂

Detector Wavelength: 254 nm

Injection Vol and Sample Solution: 0.5 mL of 4.65 g in 35 mL Methanol(133 mg/mL)

Preparative chiral SFC method B:

Instrument: Berger SFC MGII (HPW-2501)

Column: CHIRALPAK® IA 25×3 cm ID, 5 μm

Flow rate: 85.0 mL/min

Mobile Phase: 85/15/0.1, CO₂/IPA/DEA, 150 bar

Detector Wavelength: 225 nm (Lamda max)

Sample Prep and Inj. Volume: 300 μL of ˜13 mg/0.5 mL IPA (˜26 mg/mL)

Preparative chiral SFC method C

Column: CHIRALPAK® IA 25×3 cm ID, 5 μm

Flow rate: 90 mL/min

Mobile Phase: 85/15/0.1, CO₂/MeOH/DEA, 150 bar

Detector Wavelength: 270 nm (Lambda max)

Sample Prep and Inj. Volume: 300 μL of ˜90 mg/2 mL MeOH (˜45 mg/mL)

Preparative chiral SFC method D

Flow rate: 40 mL/min, 100 Bar, 35° C.

Mobile Phase: 20% Methanol/80% CO₂

Detector Wavelength: 224 nm (Lambda max)

Injection Volume: 300 μL

Sample Preparation: 10 mg dissolved in 0.5 mL MeCN (20 mg/mL);

17 mg dissolved in 0.5 mL MeCN (34 mg/mL)

Analytical chiral SFC chromatography (unless otherwise noted) wasperformed on an Aurora Analytical SFC or Berger Analytical SFC using oneof the following methods:

Analytical chiral SFC method A:

Column: CHIRALCEL it OD-H, 4.6×250 mm ID, 5 μm

Flow rate: 3.0 mL/min, 100 bar BP, 35° C.

Mobile Phase: 15% Methanol/85% CO₂

Detector Wavelength: 220 nm

Sample Solution: 1 mg/mL in methanol (concentrated/reconstituted)

Injection Volume: 10 μL

Analytical chiral SFC method B:

Column: CHIRALPAK® IA 250×4 6 mm ID, 5 μm

Flow rate: 2.0 mL/min

Mobile Phase: 85/15/0.1, CO₂/IPA/DEA, 150 bar

Detector Wavelength: 225 nm (Lamda max)

Injection Volume: 10 μL

Analytical chiral SFC method C:

Column: CHIRALPAK® IA 250×4 6 mm ID, 5 μm

Flow rate: 3.0 mL/min

Mobile Phase: 65/35/0.1, CO₂/MeOH/DEA, 150 bar

Detector Wavelength: 270 nm (Lambda max)

Injection Volume: 10 μL

Analytical chiral SFC method D:

Column: CHIRALCEL® OD, 250×4.6 mm ID, 10 μm

Flow rate: 2.0 mL/min, 100 bar, 35° C.

Mobile Phase: 20% Methanol/80% CO₂

Detector Wavelength: 223 nm

Injection Volume: 10 μL

NMR Employed in Characterization of Examples

¹H NMR spectra (unless otherwise noted) were obtained with JEOL orBruker FOURIER® transform spectrometers operating at 400 MHz or 500 MHz.¹H-nOe experiments were performed in some cases for regiochemistryelucidation with a 400 MHz Bruker FOURIER® Transform spectrometer.

Spectral data are reported as chemical shift (multiplicity, number ofhydrogens, coupling constants in Hz) and are reported in ppm (δ units)relative to either an internal standard (tetramethyl silane=0 ppm) for¹H NMR spectra, or are referenced to the residual solvent peak (2.49 ppmfor CD₃SOCD₂H, 3.30 ppm for CD₂HOD, 1.94 for CHD₂CN, 7.26 ppm for CHCl₃,5.32 ppm for CDHCl₂).

Microwave instrumentation employed in heating reactions.

BIOTAGE® Initiator 2.5, maximum power 400 W, reaction volume range0.2-10 mL. Reactions are run in sealed pressure vessels speciallymanufactured for this instrument.

Example 1.6-Methyl-2-oxo-6-phenyl-4-p-tolyl-1,2,5,6-tetrahydropyridine-3-carbonitrile

A solution of heptan-2-one (51 mg, 0.45 mmol), 1-p-tolylethanone (60 mg,0.45 mmol), ethyl-2-cyanoacetate (51 mg, 0.45 mmol) and ammonium acetate(42 mg, 0.55 mmol) in anhydrous DMF (0.6 mL) was heated with stirring at100° C. for 16 h. The reaction was diluted with EtOAc and washed withwater. The solvent was removed in vacuo and the product was purified bypreparative HPLC (MeOH/H₂O/TFA) to provide the desired product (8 mg,6%) as a white solid. LCMS Anal. Called for C₁₉H₂₄N₂O 297.41, found[M+H] 297.2. ¹H NMR (500 MHz, CDCl₃) δ 0.89 (t, J=6.87 Hz, 3H),1.24-1.40 (m, 9H), 1.51-1.71 (m, 2H) 2.42 (s, 3H), 2.73-2.97 (m, 2H),6.09 (s, 1H), 7.30 (d, J=7.70 Hz, 2H), 7.52 (d, J=7.70 Hz, 2H).

Example 2.3-(1H-Tetrazol-5-yl)-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one

Intermediate 2A. 4-(4,4,4-Trifluorobutoxy)benzaldehyde

To a solution of 4-hydroxybenzaldehyde (20 g, 164 mmol) and4,4,4-trifluorobutan-1-ol (25 g, 195 mmol) in anhydrous CH₂Cl₂ (500 mL)at 0° C. under Ar was added a solution of PPh₃ (51.5 g, 196 mmol) inCH₂Cl₂ (200 mL) over 15 min, and then DIAD (36.4 g, 180 mmol) inanhydrous CH₂Cl₂ (150 mL) was added dropwise. The mixture was stirred at0° C. for 0.5 h. The reaction was warmed to rt and stirred for another 3h. The solvent was removed in vacuo and the residue was triturated withCH₂Cl₂ three times to remove insoluble solids. The combined CH₂Cl₂washings were concentrated and the residue was purified by silica gelchromatography (330 g silica gel, eluted with EtOAc in hexanes) toprovide Intermediate 2A (27 g, 71%) as a light brown oil. LCMS Anal.Calc'd for C₁₁H₁₁F₃O₂ 232.20, found [M+H] 233.0.

Intermediate 2B.2,2,2-Trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethanol

To the solution of Intermediate 2A (26.7 g, 114 mmol) andtrimethyl(trifluoromethyl)silane (16.9 g, 119 mmol) in anhydrous DME(112 mL) was added CsF (500 mg, 3.29 mmol). The reaction was stirred atrt for 16 h. To the mixture was added 4 N aq HCl (114 mL) and thereaction was stirred at rt for 2.5 h. The reaction was diluted withEtOAc (300 mL) and washed with water, sat'd aq NaHCO₃, sat'd aq NaCl,dried over anhydrous MgSO₄, filtered and concentrated to provideIntermediate 2B (42.5 g, 122%) as an oil. The crude product was usedwithout further purification. LCMS Anal. Calc'd for C₁₂H₁₂F₆O₂ 302.21,found [M−H] 301.2.

Intermediate 2C.2,2,2-Trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethanone

To a solution of Intermediate 2B (115 mmol) in anhydrous CH₂Cl₂ (320 mL)was added Dess-Martin periodinane (50.2 g, 118 mmol) portionwise at 0°C. The reaction was stirred at 0° C. for 0.5 h then at rt for 3 h. Tothe reaction was added 100 mL of sat'd aq Na₂CO₃ and 250 mL of EtOAc.The reaction was stirred for another 2 h. The insoluble material wasremoved by filtration. The layers were separated. The organic layer waswashed with sat'd aq Na₂CO₃. Additional solids that formed upon standingovernight were removed. The organic solution was washed with sat'd aqNaCl, dried over anhydrous MgSO₄, filtered and concentrated to provide adark brown liquid, which was purified by silica gel chromatography (220g silica gel, elute with EtOAc in hexanes to provide Intermediate 2C (26g, 76%) as a colorless oil.

Intermediate 2D. Triphenylphosphoniump-tolylcarbonylylide

To a refluxing solution of PPh₃ (6.15 g, 23.47 mmol) in anhydrous THF(220 mL) under argon was added dropwise a solution of2-bromo-1-p-tolylethanone (5 g, 23.47 mmol) in THF (60 mL). The reactionwas refluxed for 2.5 h and then cooled to rt. The precipitate wascollected by filtration and rinsed with diethyl ether. The solids weresuspended in 1:1 MeOH and H₂O (500 mL), and then 2 N aq NaOH (55 mL) wasadded. The reaction was stirred at rt for 16 h. MeOH was removed invacuo and the aq solution was extracted with CHCl₃. The combined organicextracts were washed with sat'd aq NaCl, dried over anhydrous Na₂SO₄,filtered and concentrated to provide Intermediate 2D (9 g, 97%) as awhite solid. LCMS Anal. Calc'd for C₂₇H₂₃₀P 394.44, found [M+H] 395.2.

Intermediate 2E.(Z)-4,4,4-Trifluoro-1-p-tolyl-3-(4-(4,4,4-trifluorobutoxy)phenyl)but-2-en-1-one

Intermediate 2D (5.13 g, 13 mmol) and Intermediate 2C (3.90 g, 13 mmol)were suspended in DMSO (15 mL). The reaction was heated to 160° C. for1000 s under microwave conditions. The reaction was cooled to rt anddiluted with EtOAc (60 mL). The mixture was washed with water and sat'daq NaCl, dried over anhydrous MgSO₄, filtered and concentrated. Thecrude product was purified by silica gel chromatography (120 g silicagel, elute with EtOAc in hexanes to provide Intermediate 2E (5.9 g, 98%)as a light brown oil.

Intermediate 2F, isomer 1.(R)-3-Amino-4,4,4-trifluoro-1-p-tolyl-3-(4-(4,4,4-trifluorobutoxy)phenyl)-butan-1-one

Intermediate 2F, isomer 2.(S)-3-Amino-4,4,4-trifluoro-1-p-tolyl-3-(4-(4,4,4-trifluorobutoxy)phenyl)-butan-1-one

To a solution of Intermediate 2E (2.1 g, 5.04 mmol) in DMSO (50 mL) wasadded 15 N aq NH₄OH (25 mL). The mixture was stirred in sealed pressurevessel for 2 days. The reaction was diluted with EtOAc (60 mL), washedwith water and sat'd aq NaCl, dried over anhydrous MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatographycolumn (eluted with EtOAc in hexanes to provide racemic Intermediate 2F(2.2 g, 101%) as a white solid. LCMS Anal. Calc'd for C₂₁H₂₁F₆NO₂433.39, found [M+H] 434.2. Separation of the individual enantiomers ofIntermediate 2F was carried out using preparative chiral SFC method A:Racemic Intermediate 2F (2200 mg) provided Intermediate 2F, isomer 1(817 mg) and Intermediate 2F, isomer 2 (790 mg). Enantiomeric puritydetermination of Intermediate 2F, isomer 1 and 2 was carried out usinganalytical SFC method A. Intermediate 2F, isomer 1: RT=2.2 min, 99% ee.Intermediate 2F, isomer 2: RT=2.8 min, 99% ee. X-ray crystal datacollected for the camphorsulfonic acid salt of Intermediate 2F, isomer 1showed the chiral center to have the R-configuration; therefore, thechiral center for Intermediate 2F, isomer 2 has the S-configuration.

Intermediate 2G.2-(1H-Tetrazol-5-yl)-N-(1,1,1-trifluoro-4-oxo-4-p-tolyl-2-(4-(4,4,4-trifluorobutoxy)-phenyl)butan-2-yl)acetamide

To a solution of Intermediate 2F (789 mg, 1.82 mmol) in anhydrous THF (9ml) at 0° C. was added DCC (1.13 g, 5.46 mmol). 2-Tetrazole acetic acid(700 mg, 5.46 mmol) was added dropwise as a suspension in anhydrous THF(8 mL). The reaction was stirred at 0° C. for 1 h and then at rtovernight. The reaction was filtered and solids were rinsed with THF.The filtrate was diluted with EtOAc (40 mL), washed with sat'd Na₂CO₃and sat'd aq NaCl, dried over anhydrous MgSO₄, filtered and concentratedto provide Intermediate 2G (1.5 g, 152%) as a reddish brown solid.Intermediate 2G was used in the next step without further purification.LCMS Anal. Calc'd for C₂₄H₂₃F₆N₅O₃ 543.46, found [M+H] 543.9.

Example 2

To a solution of Intermediate 2G (1.5 g) in EtOH (11 mL) was addedpiperidine (0.33 mL). The reaction was heated to 78° C. for 16 h in asealed vial. The reaction was cooled to rt and the solvent was removedin vacuo. The residue was purified by preparative HPLC (MeOH/H₂O/TFA).Fractions containing the product were dried in vacuo and the product wasre-dissolved in MeOH and concentrated again. The oily brown product wasre-dissolved in CH₂Cl₂ (5 mL) and concentrated in vacuo to provideExample 2 (552 mg, 57% over 2 steps) as a reddish foam. LCMS Anal.Calc'd for C₂₄H₂₁F₆N₅O₂ 525.45, found [M+H] 526.2. ¹H NMR (500 MHz,CD₃OD) δ 7.61 (d, J=9.1 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 7.07-7.01 (m,2H), 6.90 (d, J=8.3 Hz, 2H), 4.10 (t, J=6.1 Hz, 2H), 3.84-3.64 (m, 2H),2.48-2.35 (m, 2H), 2.30 (s, 3H), 2.14-2.00 (m, 2H).

Example 2-1.(S)-3-(1H-Tetrazol-5-yl)-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one

Separation of the individual enantiomers of Example 2 was carried outusing preparative chiral SFC method C: Racemic Example 2 (89 mg)provided Example 2-1 (21 mg). Enantiomeric purity determination ofExample 2-1 was carried out using analytical SFC method C. RT=6.0 min,99% ee.

Example 2-1 can be alternatively obtained from Intermediate 2F, isomer 2using a sequence similar to one used for the conversion of Intermediate2F to Example 2.

Example 2-2.(R)-3-(1H-Tetrazol-5-yl)-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one

Separation of the individual enantiomers of Example 2 was carried outusing preparative chiral SFC method C: Racemic Example 2 (89 mg)provided Example 2-2 (22 mg). Enantiomeric purity determination ofExample 2-2 was carried out using analytical SFC method C. RT=15.1 min,99% ee.

Example 2-2 can be alternatively obtained from Intermediate 2F, isomer 1using a sequence similar to one used for the conversion of Intermediate2F to Example 2.

Example 3.6-(4-Bromophenyl)-2-oxo-4-p-tolyl-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile

Intermediate 3A.(Z)-3-(4-Bromophenyl)-4,4,4-trifluoro-1-p-tolylbut-2-en-1-one

Intermediate 2D (1.84 g, 4.74 mmol) and1-(4-bromophenyl)-2,2,2-trifluoroethanone (1.2 g, 4.74 mmol) weredissolved in THF (8 mL) and heated to 150° C. for 1000 s under microwaveconditions. The reaction was cooled to rt and the solvent was removed invacuo. The residue was purified by silica gel chromatography (24 gsilica gel, elute with EtOAc in hexanes) to yield Intermediate 3A (1.51g, 86%) as a light brown solid. LCMS Anal. Calc'd for C₁₇H₁₂BrF₃O369.18, found [M+H] 371.0.

Intermediate 3B.3-Amino-3-(4-bromophenyl)-4,4,4-trifluoro-1-p-tolylbutan-1-one

To a solution of Intermediate 3A (1.53 g, 4.14 mmol) in DMSO (23 mL) wasadded 15 N aq NH₄OH (10 mL). The reaction vessel was sealed and thereaction was stirred at rt for 16 h. Additional DMSO (3 mL) and 15 N aqNH₄OH (1 mL) were added and the reaction was stirred at rt for 16 h.Addition of DMSO (4 mL) was repeated and the reaction was stirred foranother 16 h. The solution was concentrated in vacuo followed bylyophilization to provide Intermediate 3B (1.8 g, 100%) as a brown oil.LCMS Anal. Calc'd for C₁₇H₁₅BrF₃NO 386.21, found [M+H] 388.1.

Intermediate 3C. 2-Cyanoacetyl Chloride

To a mixture of 2-cyanoacetic acid (893 mg, 10.5 mmol) and DMF (16A) inanhydrous CH₂Cl₂ (20 mL) at 0 C was added dropwise a 2 M solution ofoxalyl chloride (6 mL, 12 mmol) in CH₂Cl₂. The reaction was stirred at0° C. for 20 min, and then warmed to rt and stirred for 2 h. The solventwas removed in vacuo to provide Intermediate 3C, which was used in thenext reaction without purification.

Example 3

To a solution of Intermediate 3B (1.6 g, 4.1 mmol) in anhydrous CH₂Cl₂(15 mL) at 0° C. was added a solution of Intermediate 3C (1.1 g, 10.5mmol), pyridine (0.85 mL), and DMAP (20 mg) in anhydrous CH₂Cl₂ (5 mL).The reaction was stirred at 0° C. for 20 min, then at rt for 2.5 h. Thesolvent was removed in vacuo. The crude product was dissolved in EtOAc(30 mL), washed with sat'd aq Na₂CO₃ and sat'd aq NaCl, dried overanhydrous Na₂SO₄, filtered and concentrated to yield a brown solid. Thesolid was triturated with CH₂Cl₂/diethyl ether to provide Example 3(1.27 g) as an off white solid. The supernatant was evaporated and theresidue was purified by silica gel chromatography (eluted with EtOAc inhexanes) to provide a second batch of Example 3 (0.22 g). The combinedyield was 1.49 g (80%). LCMS Anal. Calc'd for C₂₀H₁₄BrF₃N₂O 435.24,found [M+H] 437.0. ¹H NMR (500 MHz, CDCl₃) δ 2.42 (s, 3H), 3.45-3.67 (m,2H), 7.30 (d, J=7.70 Hz, 2H), 7.39 (d, J=8.25 Hz, 2H), 7.45 (d, J=7.70Hz, 2H), 7.60 (d, J=8.80 Hz, 2H).

Example 4.6-(4-Hydroxyphenyl)-2-oxo-4-p-tolyl-6-(trifluoromethyl)-1,2,5,6-tetrahydro-pyridine-3-carbonitrile

Example 3 (1.49 g, 3.42 mmol), Pd₂dba₃ (78 mg, 0.086 mmol), KOH (403 mg,7.2 mmol) andbis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine(73 mg, 0.17 mmol) were placed in a microwave vial. The vial wasevacuated and back filled with Ar. 1,4-Dioxane (23 mL) and water (13 mL)were added to the vial and the reaction mixture was heated to 140° C.for 15 min under microwave conditions. The reaction was cooled to rt,neutralized with 1 N HCl, diluted with water, and extracted with EtOAc.The combined organic extracts were washed with water and sat'd aq NaCl,dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel chromatography to provide Example 4 (1.14 g, 85%)as a light brown solid. LCMS Anal. Calc'd for C₂₀H₁₅F₃N₂O₂ 372.34, found[M+H] 373.2. ¹H NMR (500 MHz, DMSO-d₆) δ 2.30 (s, 3H), 3.65 (q, J=18.15Hz, 2H), 6.73 (d, J=8.25 Hz, 2H), 7.28 (d, J=8.25 Hz, 2H), 7.38 (d,J=8.80 Hz, 2H), 7.47 (d, J=8.25 Hz, 2H), 9.63 (s, 1H), 9.70 (s, 1H).

Example 5.6-(4-Butoxyphenyl)-2-oxo-4-p-tolyl-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile

To a solution of Example 4 (20 mg, 0.054 mmol) and n-butanol (6 mg,0.081 mmol) in anhydrous CH₂Cl₂ (0.3 mL) under Ar was added sequentiallytriphenylphosphine (21 mg, 0.081 mmol) in CH₂Cl₂ (0.3 mL) and DEAD (14mg, 0.081 mmol) in CH₂Cl₂ (0.3 mL). The reaction mixture was stirred at0° C. under argon for 20 min, then at rt for 2 h. The solvent wasevaporated in vacuo and the product was purified by preparative HPLC(CH₃CN/H₂O/TFA) to provide Example 5 (5.6 mg, 24%). LCMS Anal. Calc'dfor C₂₄H₂₃F₃N₂O₂ 428.45, found [M+H] 429.3. ¹H NMR (500 MHz, CDCl₃) δ0.98 (t, J=7.42 Hz, 3H), 1.41-1.56 (m, 2H), 1.73-1.84 (m, 2H), 2.41 (s,3H), 3.56 (q, J=18.15 Hz, 2H), 3.92-4.03 (m, 2H), 6.94 (d, J=8.25 Hz,3H), 7.29 (d, J=8.25 Hz, 2H), 7.37 (d, J=8.80 Hz, 2H), 7.45 (d, J=7.70Hz, 2H).

Example 6.N-(4-Methoxyphenyl)-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoro-methyl)-1,2,5,6-tetrahydropyridine-3-carboxamide

Intermediate 6A. Benzyl 3-(4-(methylamino)phenylamino)-3-oxopropanoate

To a solution of monobenzyl malonate (12.2 g, 63.1 mmol) and DMF (90 μL)in anhydrous CH₂Cl₂ (100 mL) at 0° C. was added 2 M oxalyl chloride (35mL, 70 mmol) in CH₂Cl₂. The reaction was stirred at 0° C. for 30 min,then at rt for 2.5 h. The solvent was removed in vacuo to providefreshly prepared acid chloride. This was dissolved in anhydrous CH₂Cl₂(50 mL) and added dropwise to a solution of 4-methoxyaniline (7.76 g, 63mmol) in anhydrous CH₂Cl₂ (50 mL) at 0° C. followed by the addition ofpyridine (5.35 mL, 66.2 mmol). The reaction was stirred at 0° C. for 0.5h, then at rt overnight. The reaction was washed with water and sat'd aqNaCl, dried over anhydrous MgSO₄, filtered and concentrated. The residuewas triturated with EtOAc/CH₂Cl₂ to yield the first batch ofIntermediate 6A as a light brown solid (6.95 g). The supernatant wasevaporated and the residue was purified by silica gel chromatography(eluted with EtOAc in hexanes) to provide a second batch of Intermediate6A as a light brown solid (7.4 g). The combined yield was 14.4 g (76%).LCMS Anal. Calc'd for C₁₇H₁₈N₂O₃ 298.34, found [M+H] 300.2.

Intermediate 6B. 3-(4-Methoxyphenylamino)-3-oxopropanoic acid

To a solution of Intermediate 6A (14.4 g, 4.8 mmol) in 10:1 EtOAc/MeOH(220 mL) was added 10% Pd/C (250 mg). The reaction mixture was stirredvigorously under an atmosphere of hydrogen (40 psi) for 2 h. More 10%Pd/C (250 mg) was added and the reaction was stirred under 50 psihydrogen for another 1 h. Additional 10% Pd/C (500 mg) was added and thereaction was stirred under 50 psi hydrogen for an additional 1 h. Thereaction was filtered through a pad of Celite® and the filtrate wasconcentrated in vacuo to yield Intermediate 6B (11.1 g, 96%) as anoff-white solid. LCMS Anal. Calc'd for C₁₀H₁₁NO₄ 209.20, found [M+H]210.1.

Intermediate 6C.N¹-(4-Methoxyphenyl)-N³-(1,1,1-trifluoro-4-oxo-4-p-tolyl-2-(4-(4,4,4-trifluoro-butoxy)phenyl)-butan-2-yl)malonamide

To triphenylphosphine (8.42 g, 32.1 mmol) in anhydrous CH₂Cl₂ (70 mL)was added Intermediate 6B (2.24 g, 10.7 mmol) in anhydrous CH₂Cl₂ (30mL) followed by trichloroacetonitrile (1.86 g, 12.8 mmol). The mixturewas stirred at rt for 3 h. The freshly prepared acid chloride was addedto a solution of Intermediate 2F (1.13 g, 2.61 mmol) in anhydrous CH₂Cl₂(20 mL), followed by the addition of pyridine (1.04 mL, 1.02 g, 12.85mmol). The reaction was stirred at rt under argon overnight. Thereaction was cooled to 0° C. and MeOH (40 mL) was added. The reactionwas stirred at 0° C. for 10 min, then at rt for 30 min. The solvent wasremoved in vacuo and the crude product was purified by silica gelchromatography (120 g silica gel, eluted with EtOAc in hexanes). Productand triphenylphosphine oxide co-eluted. Fractions containing both werecombined and evaporated to dryness. The solids were triturated withhexanes/EtOAc to remove most of the triphenylphosphine oxide. Theproduct was again purified by silica gel chromatography (40 g silicagel, eluted with EtOAc in hexanes) to provide Intermediate 6C (1.03 g,63%) as a brown oil. LCMS Anal. Calc'd for C₃₁H₃₀F₆N₂O₅ 624.57, found[M+H] 625.3.

Example 6

To a solution of Intermediate 6C (1.03 g, 1.65 mmol) in MeOH (10 mL) wasadded piperidine (100 μL, 1.01 mmol). The reaction was stirred at 75° C.for 1 h. The solvent was removed in vacuo and the crude product waspurified by silica gel chromatography (120 g silica gel, eluted withEtOAc in hexanes). Mixed fractions from the first column were purifiedagain by silica gel chromatography (40 g silica gel, eluted with EtOAcin hexanes) to provide Example 6 (546 mg, 55%) as a off-white solid.LCMS Anal. Calc'd for C₃₁H₂₈F₆N₂O₄ 606.56, found [M+H] 607.3. ¹H NMR(500 MHz, CD₃OD) δ 1.97-2.08 (m, 2H), 2.30 (s, 3H), 2.32-2.44 (m, 2H),3.45-3.67 (m, 2H), 3.72 (s, 3H), 4.06 (t, J=6.05 Hz, 2H), 6.77 (d,J=9.35 Hz, 2H), 6.97 (d, J=8.80 Hz, 2H), 7.13-7.24 (m, 4H), 7.28 (d,J=8.25 Hz, 2H), 7.52 (d, J=8.80 Hz, 2H).

Example 6-1.(R)—N-(4-Methoxyphenyl)-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoro-methyl)-1,2,5,6-tetrahydropyridine-3-carboxamide

Example 6-1 was prepared using a procedure analogous to Example 6 byreplacing Intermediate 2F with Intermediate 2F, isomer 1.

Example 6-2.(S)—N-(4-Methoxyphenyl)-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoro-methyl)-1,2,5,6-tetrahydropyridine-3-carboxamide

Example 6-2 was prepared using a procedure analogous to Example 6 byreplacing Intermediate 2F with Intermediate 2F, isomer 2.

Example 7.6-(4-(6-Ethoxypyridin-3-yl)phenyl)-2-oxo-4-p-tolyl-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile

To a solution of Example 3 (20 mg, 0.046 mmol), 6-ethoxypyridin-3-ylboronic acid (11 mg, 0.07 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 10 mol %) in DMF (0.6 mL) sparged with Ar was added2 N aq K₂CO₃ (46 μL, 0.096 mmol). The vessel was sealed and the reactionheated to 80° C. for 22 h. The reaction was cooled to rt and the productwas purified twice by preparative HPLC (CH₃CN/H₂O/TFA and CH₃OH/H₂O/TFAsequentially) to provide Example 7 (10 mg, 45%) as a light brown solid.LCMS Anal. Calc'd for C₂₇H₂₂F₃N₃O₂ 477.48, found [M+H] 478.3. ¹H NMR(500 MHz, CD₃OD) δ 1.40 (t, J=6.87 Hz, 3H), 2.40 (s, 3H), 3.71-3.88 (m,2H), 4.37 (q, J=7.15 Hz, 2H), 6.94 (d, J=8.25 Hz, 1H), 7.33 (d, J=7.70Hz, 2H), 7.54 (d, J=8.25 Hz, 2H), 7.66-7.78 (m, 4H), 8.05 (dd, J=8.80,2.20 Hz, 1H), 8.42 (d, J=2.20 Hz, 1H).

Example 8.(S)-3-(2H-Tetrazol-5-yl)-4-p-tolyl-6-(4-(6,6,6-trifluorohexyloxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one

Intermediate 8A. 4-(6,6,6-Trifluorohexyloxy)benzaldehyde

To a suspension of 4-hydroxybenzaldehyde (488 mg, 4 mmol) and6-bromo-1,1,1-trifluorohexane (657 mg, 3 mmol) in MeCN (10 mL) was addedK₂CO₃ (829 mg, 6.00 mmol). The resulting mixture was reflux overnight.Insoluble material was filtered off and rinsed with MeCN. The combinedfiltrate was concentrated to afford a white solid. This white solid waspartitioned between EtOAc and 1 N NaOH solution. The organic layer wasseparated, washed with sat'd NH₄Cl, dried over MgSO₄, filtered andconcentrated to afford Intermediate 8A as a clear liquid. LCMS Anal.Calc'd for C₁₃H₁₅F₃O₂ 260.10, found [M+H] 261.0.

Intermediate 8B.2,2,2-Trifluoro-1-(4-(6,6,6-trifluorohexyloxy)phenyl)ethanone

Intermediate 8B was prepared using a procedure analogous to Intermediate2C except that Intermediate 2A was replaced with Intermediate 8A. ¹H NMR(500 MHz, CDCl₃) δ 8.06-8.02 (m, 2H), 6.99-6.97 (m, 1H), 4.08 (t, J=6.2Hz, 2H), 2.19-2.06 (m, 2H), 1.92-1.82 (m, 2H), 1.71-1.55 (m, 4H).

Intermediate 8C.(S,E)-2-Methyl-N-(2,2,2-trifluoro-1-(4-(6,6,6-trifluorohexyloxy)phenyl)ethylidene)propane-2-sulfinamide

To a solution of Intermediate 8B (717 mg, 2.184 mmol) and(S)-2-methylpropane-2-sulfinamide (529 mg, 4.37 mmol) in THF (10 mL) wasadded tetraethoxytitanium (1993 mg, 8.74 mmol) in THF (20 mL). Theresulting mixture was reflux for 5 h. TLC (20% EtOAc in hexane)indicated the starting ketone was completely consumed. The solvent wasevaporated to afford a yellow oil. This yellow oil was dissolved inEtOAc and then washed with saturated NaHCO₃ (25 mL) and a large amountof white precipitation formed which was removed by filtering through abed of Celite®. The white precipitation was rinsed with EtOAc. Thecombined EtOAc solution was washed again with saturated NaHCO₃, dried(MgSO₄) and concentrated. The crude product was purified by silica gelchromatography (40 g silica gel, eluted with EtOAc in hexanes) to affordIntermediate 8C (620 mg, 66%).

Intermediate 8D.(S)-2-Methyl-N—((S)-1,1,1-trifluoro-4-oxo-4-p-tolyl-2-(4-(6,6,6-trifluorohexyloxy)phenyl)butan-2-yl)propane-2-sulfinamide

To a solution of 1-(p-tolyl)ethanone (609 mg, 4.31 mmol) in THF (10 mL)was cooled to −78° C. and to this solution was added lithiumbis(trimethylsilyl)amide (4.31 mL, 4.31 mmol). The resulting mixture wasstirred at −78° C. for 20 min and then

Intermediate 8C (620 mg, 1.437 mmol) in THF (3 mL) was added dropwise.The resulting mixture was stirred at −78° C. for 1.5 h and then at 0° C.for 1.5 h. The reaction was quenched with NH₄Cl and concentrated. Thecrude product was purified by silica gel chromatography (80 g silicagel, eluted with EtOAc in hexanes) to afford Intermediate 8D (482 mg,59%) as the slower eluting diastereomer on silica gel column. LCMS Anal.Calc'd for C₂₇H₃₃F₆NO₃S 565.21, found [M+H] 566.0.

Intermediate 8E.(S)-3-Amino-4,4,4-trifluoro-1-p-tolyl-3-(4-(6,6,6-trifluorohexyloxy)phenyl)butan-1-one

To a solution of Intermediate 8D (482 mg, 0.852 mmol) in MeOH (4 mL) wasadded 4 M HCl (1 mL, 4.00 mmol) in dioxane. The resulting mixture wasstirred at rt for 2 h and then concentrated. The residue was taken up inEtOAc, washed with saturated NaHCO₃ and brine, dried (MgSO₄), filteredand concentrated to afford Intermediate (386 mg, 58%) as a colorlessoil, which was used for the subsequent reaction without furtherpurification. LCMS Anal. Calc'd for C₂₃H₂₅F₆NO₂ 461.18, found [M+H]461.9.

Example 8

To a solution of Intermediate 8E (140 mg, 0.303 mmol) and2-(2H-tetrazol-5-yl)acetic acid (117 mg, 0.910 mmol) in THF (3 mL) at 0°C. was added DCC (188 mg, 0.910 mmol). The resulting mixture was stirredovernight. The solvent was evaporated and the crude mixture was taken upin EtOAc. The organic solution was washed with saturated NaHCO₃, 1 N HCland brine, dried (MgSO₄), filtered and concentrated to afford a brownoil. This oil was dissolved in EtOH (3 mL) and added piperidine (300 μL,3.03 mmol). The resulting mixture was stirred at 80° C. overnight. Thereaction mixture was diluted with MeOH and purified by preparative HPLC(MeCN/H₂O/TFA) to yield Example 8 (86 mg, 51%) as a solid. LCMS Anal.Calc'd for C₂₆H₂₅F₆N₅O₂ 553.19, found [M+H] 554.0. ¹H NMR (500 MHz,CDCl₃) δ 7.46 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.0 Hz, 3H), 7.02-6.93 (m,4H), 3.99 (t, J=6.3 Hz, 2H), 3.68-3.56 (m, 2H), 2.39 (s, 3H), 2.19-2.07(m, 2H), 1.89-1.79 (m, 2H), 1.71-1.63 (m, 2H), 1.62-1.53 (m, 2H).

Example 9.3-(2-Ethyl-2H-tetrazol-5-yl)-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one

To Example 2 (30 mg, 0.057 mmol) in anhydrous CH₂Cl₂ (0.6 mL) was addediodoethane (9 mg, 0.057 mmol) and triethylamine (24 μL, 0.17 mmol). Thereaction was heated to 120° C. for 10 min under microwave conditions.The solvent was evaporated in vacuo and the residue was purified bypreparative HPLC (CH₃CN/H₂O/TFA) to provide Example 9 (2.3 mg, 7%) as alight brown solid. LCMS Anal. Calc'd for C₂₆H₂₅F₆N₅O₂ 553.50, found[M+H] 554.3. ¹H NMR (500 MHz, CDCl₃) δ 1.51 (t, J=7.42 Hz, 2H),1.98-2.13 (m, 2H), 2.21-2.39 (m, 5H), 3.51 (d, J=17.60 Hz, 1H), 3.72 (d,J=17.60 Hz, 1H), 4.04 (t, J=6.05 Hz, 2H), 4.56 (q, J=7.52 Hz, 2H) 6.87(d, J=8.25 Hz, 2H), 6.95 (d, J=8.80 Hz, 2H), 7.02 (d, J=8.25 Hz, 2H),7.46 (d, J=8.80 Hz, 2H), 7.93 (s, 1H).

Example 10.4-p-Tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-3-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-5,6-dihydropyridin-2(1H)-one

To Example 2 (29 mg, 0.055 mmol) in anhydrous CH₂Cl₂ (0.3 mL) was addeda solution of trifluoroacetic anhydride (23.2 mg, 0.11 mmol) inanhydrous CH₂Cl₂ (0.2 mL) dropwise. The mixture was stirred at rt for 4h and then concentrated. The residue was purified by preparative HPLC toprovide Example 10 (19 mg, 58%) as a white solid. LCMS Anal. Calc'd forC₂₆H₂₀F₉N₃O₃ 593.44, found [M+H] 594.2. ¹H NMR (500 MHz, CD₃OD) δ1.97-2.11 (m, 2H), 2.31 (s, 3H), 2.34-2.44 (m, 2H), 3.64-3.88 (m, 2H),4.08 (t, J=6.05 Hz, 2H), 6.98 (d, J=8.25 Hz, 2H), 7.03 (d, J=8.80 Hz,2H), 7.16 (d, J=8.25 Hz, 2H), 7.57 (d, J=8.80 Hz, 2H).

Example 11.6-Methyl-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-N-(4-(trifluoromethoxy)-phenyl)-1,2,5,6-tetrahydropyridine-3-carboxamide

Intermediate 11A. 1-Bromo-4-(4,4,4-trifluorobutoxy)benzene

To a solution of 4-bromophenol (2.2 g, 12.7 mmol) and4-bromo-1,1,1-trifluorobutane (2.4 g, 12.7 mmol) in anhydrous DMF (15mL) was added K₂CO₃ (3.5 g, 25.4 mmol). The mixture was stirred at rtovernight. The mixture was diluted with EtOAc (120 mL) and the solidswere removed by filtration. The filtrate was washed with water and sat'daq NaCl, dried over anhydrous MgSO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography (40 g silica gel,eluted with EtOAc in hexanes) to provide Intermediate 11A (3.05 g, 85%)as a colorless oil.

Intermediate 11B. (E)-Ethyl3-(4-(4,4,4-trifluorobutoxy)phenyl)but-2-enoate

Intermediate 11A (2.81 g, 9.93 mmol), (E)-ethyl but-2-enoate (1.25 g,10.9 mmol), palladium(II) acetate (0.11 g, 0.5 mmol), tetraethylammoniumchloride (1.65 g, 9.9 mmol), N-cyclohexyl-N-methylcyclohexanamine (2.91g, 14.9 mmol) and dimethylacetamide (30 ml) were placed in a oven-driedvial and sparged with argon for 5 min. The vial was sealed and thereaction heated to 110° C. for 6 h. The reaction was cooled to rt,diluted with EtOAc (75 mL), washed with water and sat'd aq NaCl, driedover anhydrous MgSO₄, filtered and concentrated. The residue waspurified by silica gel chromatography eluting with EtOAc in hexanes toprovide Intermediate 11B (1.81 g, 49%) as a colorless oil. LCMS Anal.Calc'd for C₁₆H₁₉F₃O₃ 316.32, found [M+H] 317.2.

Intermediate 11C.(E)-N-Methoxy-N-methyl-3-(4-(4,4,4-trifluorobutoxy)phenyl)but-2-enamide

A solution of Intermediate 11B (2.67 g, 8.44 mmol) andN,O-dimethylhydroxylamine hydrochloride (1.65 g, 16.9 mmol) in anhydrousTHF (35 mL) was cooled to −61° C. (CHCl₃/dry ice) under an atmosphere ofAr. To this solution was added 0.5 M isopropylmagnesium chloride (16.9mL, 33.8 mmol) in THF slowly via a syringe. The reaction was stirred at−61° C. for 1.5 h, warmed to −20° C. (sat'd aq NaCl/ice) and stirred for40 min, then warmed to 0° C. and stirred for 20 min. The reaction waspoured into 10 mL of sat'd aq NH₄Cl and 12 mL of water, and thenextracted with EtOAc. The organic layer was washed with sat'd aq NaCl,dried over anhydrous MgSO₄, filtered and concentrated. The residue waspurified by silica gel chromatography eluting with EtOAc in hexanes toprovide Intermediate 11C (1.62 g, 58%) as a light brown oil. LCMS Anal.Calc'd for C₁₆H₂₀F₃NO₃ 331.33, found [M+H] 332.2.

Intermediate 11D.(E)-1-p-Tolyl-3-(4-(4,4,4-trifluorobutoxy)phenyl)but-2-en-1-one

To a solution of Intermediate 11C (1.62 g, 4.89 mmol) in anhydrous THF(25 mL) at −78° C. was added dropwise 0.5 Mp-tolylmagnesium bromide inether (25 mL, 12.5 mmol). The reaction was stirred at −78° C. for 40min, then gradually warmed to rt. The reaction was poured into 1:1 sat'daq NH₄Cl and water (60 mL). The mixture was extracted with EtOAc. Theorganic layer was washed with sat'd aq NaCl, dried over MgSO₄, filteredand concentrated. The residue was purified by silica gel chromatography(eluted with EtOAc in hexanes) to provide Intermediate 11D (1.34 g, 76%)as a light brown solid. LCMS Anal. Calc'd for C₂₁H₂₁F₃O₂ 362.39, found[M+H] 363.2. ¹H NMR (500 MHz, CDCl₃) δ 2.01-2.11 (m, 2H), 2.29-2.37 (m,2H), 2.42 (s, 3H), 2.58 (s, 3H), 4.07 (t, J=6.05 Hz, 2H), 6.92 (d,J=8.80 Hz, 2H), 7.14 (s, 1H), 7.23-7.34 (m, J=8.25 Hz, 2H), 7.55 (d,J=8.80 Hz, 2H), 7.90 (d, J=8.25 Hz, 2H).

Intermediate 11E.3-Amino-1-p-tolyl-3-(4-(4,4,4-trifluorobutoxy)phenyl)butan-1-one

Ammonia was bubble into a solution of Intermediate 11D (1.34 mg, 0.64mmol) in EtOH (20 mL) and DMSO (12 mL) for 10 min at 0° C. The reactionwas stirred at rt overnight in a sealed pressure vessel. Analytical HPLCshowed reaction to have progressed only ca. 10%. The mixture was cooledto −15° C., then ammonia was bubbled through for 7 min. The vessel wassealed and the reaction was stirred at rt overnight. Analytical HPLCshowed the reaction to be ca. 25-30% complete. The mixture was dilutedwith EtOAc (75 mL), washed with water and sat'd aq NaCl, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography to provide Intermediate 11E (281mg, 20%) as a light brown oil. LCMS Anal. Calc'd for C₂₁H₂₄F₃NO₂ 379.42,found [M+H] 380.3.

Intermediate 11F. 3-Oxo-3-(4-(trifluoromethoxy)phenylamino)propanoicacid

By sequential application of the procedures for Intermediates 6A and 6B,4-trifluoromethoxyaniline (2.3 g, 13 mmol) was converted to Intermediate11F (2.8 g, 11 mmol), which was isolated as a white solid. LCMS Anal.Calc'd for C₁₀H₈F₃NO₄ 263.17, found [M+H] 264.1.

Intermediate 11G.N¹-(4-Oxo-4-p-tolyl-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)-N³-(4-(trifluoromethoxy)-phenyl)malonamide

To a solution of Intermediate 11F (41.6 mg, 0.158 mmol) in anhydrousCH₂Cl₂ (0.6 mL) was added PPh₃ (124 mg, 0.474 mmol) followed by dropwiseaddition of trichloroacetonitrile (27.4 mg, 0.19 mmol). The reaction wasstirred at rt for 3 h. To the freshly prepared acid chloride was added asolution of Intermediate 11E (20 mg, 0.053 mmol) in anhydrous CH₂Cl₂(0.3 mL) followed by pyridine (19.4, 0.237 mmol). The mixture wasstirred at rt overnight. The solvent was removed in vacuo. The productwas purified by preparative HPLC (MeOH/H₂O/TFA) to yield Intermediate11G (11 mg, 33%) as a brown solid. LCMS Anal. Calc'd for C₃₁H₃₀F₆N₂O₅624.57, found [M+H] 625.4.

Example 11

To a solution of Intermediate 11G (11 mg, 0.018 mmol) in MeOH (0.8 ml)was added piperidine (15.4). The reaction was stirred at 75° C. for 1.5h. The product was isolated by preparative HPLC (CH₃CN/H₂O/TFA) toprovide Example 11 (5.2 mg, 44%) as a brown solid. LCMS Anal. Calc'd forC₃₁H₂₈F₆N₂O₄ 606.56, found [M+H] 607.4. ¹H NMR (500 MHz, CD₃OD) δ 1.68(s, 3H), 1.95-2.07 (m, 2H), 2.27 (s, 3H), 2.30-2.41 (m, 2H), 3.11-3.26(m, 2H), 4.03 (t, J=6.05 Hz, 2H), 6.91 (d, J=8.80 Hz, 2H), 7.08-7.18 (m,4H), 7.22 (d, J=8.25 Hz, 2H), 7.38 (d, J=8.80 Hz, 2H), 7.45 (d, J=8.80Hz, 2H).

Example 12.3-(2H-Tetrazol-5-yl)-4-p-tolyl-6-(trifluoromethyl)-6-(1-(5,5,5-trifluoropentyl)-1H-pyrazol-4-yl)-5,6-dihydropyridin-2(1H)-one

Intermediate 12A. 4-Iodo-1-(5,5,5-trifluoropentyl)-1H-pyrazole

To a stirred solution of 4-iodo-1H-pyrazole (337 mg, 1.737 mmol) in DMF(10 mL) was added sodium hydride (104 mg, 2.61 mmol). After 30 min,5-bromo-1,1,1-trifluoropentane (427 mg, 2.085 mmol) was added. Thereaction was stirred at rt for 2 h. 3:1 hexane:ether and water wereadded. The organic layer was washed with H₂O, dried over MgSO₄, filteredand concentrated in vacuo. The crude product was purified by silica gelchromatography (24 g silica gel, eluted with 0-60% EtOAc in hexanes) togive the desired product (460 mg, 83%) as clear oil. LCMS Anal. Calc'dfor C₈H₁₀F₃₁N₂ 318.0, found [M+H] 319.0. ¹H NMR (400 MHz, CDCl₃) δ 7.49(s, 1H), 7.40 (s, 1H), 4.12 (t, J=6.9 Hz, 2H), 2.00-2.15 (m, 2H),1.85-1.96 (m, 2H), 1.47-1.61 (m, 2H).

Intermediate 12B.2,2,2-Trifluoro-1-(1-(5,5,5-trifluoropentyl)-1H-pyrazol-4-yl)ethanone

To a stirred solution of Intermediate 12A (460 mg, 1.446 mmol) intetrahydrofuran (5 mL) at 0° C. was added isopropylmagnesium chloride(0.795 mL, 1.591 mmol) quickly. After 30 min, additional 0.25 eq ofiPrMgCl was added and after 30 min, the mixture was cooled to −78° C.2,2,2-Trifluoro-1-(piperidin-1-yl)ethanone (288 mg, 1.591 mmol) wasadded quickly and the reaction was warmed to rt and stirred for 3 h. Thereaction was quenched with sat'd aq NH₄Cl and diluted with EtOAc. Theorganic layer was washed with sat'd aq NH₄Cl, dried over MgSO₄, filteredand concentrated in vacuo. The crude product was purified by silica gelchromatography (40 g silica gel, eluted with 0-100% EtOAc in hexanes) togive the desired product (265 mg, 64%) as clear oil. ¹H NMR (500 MHz,CDCl₃) δ 8.08 (s, 2H), 4.22 (t, J=7.0 Hz, 2H), 2.07-2.20 (m, 2H),1.98-2.05 (m, 2H), 1.55-1.65 (m, 2H).

Example 12

Example 12 was prepared using a procedure analogous to Example 2 byreplacing Intermediate 2C with Intermediate 12B. LCMS Anal. Calc'd forC₂₂H₂₁F₆N₇O 513.2, found [M+H] 514.3. ¹H NMR (500 MHz, CDCl₃) δ 7.75 (s,1H), 7.63 (s, 1H), 7.54-7.59 (m, 1H), 7.06 (d, J=8.0 Hz, 2H), 6.88 (d,J=8.0 Hz, 2H), 4.16 (t, J=7.0 Hz, 2H), 3.58 (d, J=18.2 Hz, 1H), 3.39 (d,J=17.9 Hz, 1H), 2.28 (s, 3H), 2.02-2.17 (m, 2H), 1.93 (quin, J=7.4 Hz,2H), 1.46-1.55 (m, 2H).

Example 13.3-Nitro-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one

Intermediate 13A.2-Nitro-N-(1,1,1-trifluoro-4-oxo-4-p-tolyl-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)-acetamide

To a solution of Intermediate 2F (130 mg, 0.3 mmol) in anhydrous THF (1mL) at 0° C. was added DCC (204 mg, 0.99 mmol) followed by a solution of2-nitroacetic acid (104 mg, 0.99 mmol) in anhydrous THF (0.5 mL)dropwise. The reaction was stirred at 0° C. for 1 h then at rtovernight. The reaction was heated to 70° C. for 4 h. The reaction wascooled to rt and diluted with EtOAc (3 mL). The solids were filtered offand the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography (eluted with EtOAc in hexanes) to provideIntermediate 13A (129 mg, 83%) as a brown oil. LCMS Anal. Calc'd forC₂₃H₂₂F₆N₂O₅ 520.42, found [M+H] 521.1.

Example 13

To a solution of Intermediate 13A (126 mg, 0.24 mmol) in MeOH (2 mL) wasadded piperidine (35 μL). The reaction mixture was heated at 75° C. for1.5 h. The product was isolated by preparative HPLC (MeOH/H₂O/TFA) toprovide Example 13 (21 mg, 17%) as a off-white solid. LCMS Anal. Calc'dfor C₂₃H₂₀F₃N₂O₄ 502.41, found [M+H] 503.1. ¹H NMR (500 MHz, CD₃OD) δ1.98-2.08 (m, 2H), 2.28-2.45 (m, 5H), 3.58 (d, J=17.60 Hz, 1H), 3.76 (d,J=17.60 Hz, 1H), 4.08 (t, J=6.05 Hz, 2H), 7.02 (d, J=8.80 Hz, 2H),7.12-7.19 (m, 2H), 7.22-7.30 (m, 2H), 7.53 (d, J=8.80 Hz, 2H).

Example 14.8-(4-Methoxyphenyl)-6-oxo-4-(4-(4,4,4-trifluorobutoxy)phenyl)-4-(trifluoro-methyl)-5-azaspiro[2.5]oct-7-ene-7-carbonitrile

Intermediate 14A. Methyl3-oxo-3-(4-(4,4,4-trifluorobutoxy)phenyl)propanoate

To a solution of methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (7.8 g, 40.2mmol) and 4,4,4-trifluorobutan-1-ol (5.15 g, 40.2 mmol) in CH₂Cl₂ (201mL) at 0° C. was added triphenylphosphine (12.6 g, 48.2 mmol). Themixture was stirred for a few min, and then DIAD (9.37 mL, 48.2 mmol)was added. The reaction was stirred at 0° C. for 30 min, then warmed tort and stirred for 3 days. The reaction was loaded directly onto a 300 gsilica gel column and eluted with EtOAc in hexanes. Fractions containingthe product were combined and concentrated to provide Intermediate 14A(9.9 g, 80%) as a colorless solid. ¹H NMR (500 MHz, CDCl₃) δ 2.03-2.13(m, 2H), 2.26-2.39 (m, 2H), 3.75 (s, 3H), 3.96 (s, 2H), 4.09 (t, J=6.05Hz, 2H), 6.92-6.96 (m, 2H), 7.86-7.97 (m, 2H).

Intermediate 14B. Methyl1-(4-(4,4,4-trifluorobutoxy)benzoyl)cyclopropanecarboxylate

To a solution of Intermediate 14A (6.0 g, 19.7 mmol) in DMF (197 mL) wasadded K₂CO₃ (8.18 g, 59.2 mmol) followed by 1,2-dibromoethane (2.6 mL,30 mmol). The reaction mixture was stirred at rt for 2 days. Thereaction was reduced in volume in vacuo, then diluted with EtOAc, washedwith a 1:1 solution of sat'd aq NaCl and water, dried over anhydrousMgSO₄, filtered and concentrated. The product was isolated by silica gelchromatography (220 g silica gel, eluted with EtOAc in hexanes) toprovide Intermediate 14B (4.2 g, 61%) as a colorless oil. ¹H NMR (500MHz, CDCl₃) δ 1.45-1.49 (m, 2H), 1.56-1.61 (m, 2H), 2.03-2.14 (m, 2H),2.26-2.39 (m, 2H), 3.60 (s, 3H), 4.09 (t, J=6.05 Hz, 2H), 6.90-6.94 (m,2H), 7.86-7.93 (m, 2H).

Intermediate 14C. Methyl1-((benzylimino)(4-(4,4,4-trifluorobutoxy)phenyl)methyl)cyclopropanecarboxylate

To a solution of Intermediate 14B (4.2 g, 13 mmol) and benzylamine (5.5mL, 50 mmol) in diethyl ether (63 mL) at 0° C. was added 1.0 M TiCl₄ inCH₂Cl₂ (7.6 mL, 7.5 mmol). The reaction was stirred at 0° C. for a fewminutes, then warmed to rt and stirred for 16 h. Celite® was added tothe reaction and the solids were removed by filtering through a bed ofCelite®. The filtrate was concentrated and purified by silica gelchromatography (120 g silica gel, eluted with EtOAc in hexanes) toprovide Intermediate 14C (4.6 g, 83%) as a colorless oil. ¹H NMR (500MHz, CDCl₃) δ 7.82 (d, J=8.8 Hz, 2H), 7.42-7.38 (m, 2H), 7.34 (t, J=7.7Hz, 2H), 7.27-7.24 (m, 1H), 6.87 (d, J=8.8 Hz, 2H), 4.90 (s, 2H), 4.04(t, J=6.0 Hz, 2H), 3.69 (s, 3H), 2.39-2.26 (m, 2H), 2.11-2.02 (m, 2H),1.78-1.72 (m, 2H), 1.11 (d, J=3.3 Hz, 2H).

Intermediate 14D. Methyl1-(1-(benzylamino)-2,2,2-trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethyl)-cyclopropanecarboxylate

To a solution of Intermediate 14C (4.6 g, 11 mmol) in acetonitrile (22mL) and DMF (2.6 mL, 33 mmol) at 0° C. was added neat TFA (1.1 mL, 13.7mmol) followed by potassium hydrogen fluoride (0.64 g, 8.2 mmol). Thereaction was stirred for ca. 5 min, thentrimethyl(trifluoromethyl)silane (2.4 mL, 16.4 mmol) was added and thereaction was warmed to rt and stirred for 16 h. Sat'd aqueous NaHCO₃ wasadded to the reaction and the mixture was extracted with EtOAc. Thecombined organic extracts were washed with sat'd aq NaCl, dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (220 g silica gel, eluted with EtOAc in hexanes) toprovide Intermediate 14D (1.8 g, 31%) as an oil. LCMS Anal. Calc'd forC₂₄H₂₅F₆NO₃ 489.45, found [M+H] 490.1.

Intermediate 14E.1-(1-(Benzylamino)-2,2,2-trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethyl)-cyclopropanecarboxylic acid

To a solution Intermediate 14D (558 mg, 1.140 mmol) in pyridine (5.7 mL)was added lithium iodide (1.53 g, 11.4 mmol). The reaction was heated toreflux overnight. The reaction was cooled to rt and diluted with waterand EtOAc. The aqueous layer was made acidic with 1 N HCl and the layerswere separated. The organic layer was washed with sat'd aq NaCl, driedover MgSO₄, filtered and concentrated to provide Intermediate 14E (506mg, 84%) which was used in the next step without further purification.LCMS Anal. Calc'd for C₂₃H₂₃F₆NO₃ 475.42, found [M+H] 476.2.

Intermediate 14F.5-Benzyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5-azaspiro[2.3]-hexan-4-one

To a solution of Intermediate 14E (506 mg, 1.1 mmol) in CH₂Cl₂ (11 mL)was added oxalyl chloride (0.12 mL, 2.2 mmol) followed by several dropsof DMF. The reaction was stirred at rt for 16 h. The solvent was removedin vacuo and the residue was purified by silica gel chromatography (24 gsilica gel, eluted with EtOAc in hexanes) to provide Intermediate 14F(389 mg, 72%) as a yellow oil. LCMS Anal. Calc'd for C₂₃H₂₁F₆NO₂ 457.41,found [M+H] 458.2.

Intermediate 14G.(1-(1-(Benzylamino)-2,2,2-trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethyl)-cyclopropyl)-(4-methoxyphenyl)methanone

Magnesium turnings (130 mg, 5.4 mmol) were suspended in anhydrous THF(13 mL). 4-Bromoanisole (1 g, 670 μL, 5.4 mmol) was added followed by afew drops of 1,2-dibromoethane. The reaction mixture was stirred at rtfor 1.5 h after which most of the magnesium had dissolved. The reactionwas warmed to 50° C. for 30 min, then cooled to rt. Final concentrationof the Grignard reagent was 0.4 M assuming complete conversion. To acold solution (−40° C.) of Intermediate 14F (200 mg, 0.44 mmol) in THF(4.4 mL) was added the freshly prepared Grignard reagent. The reactionwas warmed from −40° C. to rt, then heated to reflux overnight. Thereaction was cooled to room temperature and quenched with sat'd aqNH₄Cl. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organic extracts were washed with sat'd aqNaCl, dried over MgSO₄, filtered and concentrated. The product wasisolated using preparative HPLC (MeOH/H₂O/TFA). Fractions containing theproduct were combined and reduced in volume in vacuo. The resultingaqueous solution was made basic with sat'd aq NaHCO₃ and extracted withEtOAc. The combined organic extracts were washed with sat'd aq NaCl,dried over Na₂SO₄, filtered and concentrated to provide Intermediate 14G(6.1 mg, 2.5%). LCMS Anal. Calc'd for C₃₀H₂₉F₆NO₃ 565.55, found [M+H]566.3.

Intermediate 14H.(1-(1-Amino-2,2,2-trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethyl)cyclopropyl)(4-methoxy-phenyl)methanone

To a solution of Intermediate 14G (6 mg, 10.6 μmol) in MeOH (1 mL)containing 4.4% formic acid was added 10% palladium on carbon (2 mg, 2μmol). The reaction was stirred at rt overnight. The reaction wasfiltered through Celite®. The filtrate was made basic with sat'd aqNaHCO₃, and then evaporated to remove MeOH. The aqueous residue wasdiluted with sat'd aq NaCl and extracted with EtOAc. The combinedorganic extracts were washed with sat'd aq NaCl, dried over Na₂SO₄,filtered and concentrated to provide Intermediate 14H (4 mg, 71%) as atan glass. LCMS Anal. Calc'd for C₂₃H₂₃F₆NO₃ 475.42, found [M+H] 476.2.

Intermediate 14I.2-Cyano-N-(2,2,2-trifluoro-1-(1-(4-methoxybenzoyl)cyclopropyl)-1-(4-(4,4,4-trifluorobutoxy)-phenyl)ethyl)acetamide

To a solution of 2-cyanoacetic acid (320 mg, 3.8 mmol) in CH₂Cl₂ (9.1mL) was added oxalyl chloride (523 mg, 360 μL, 4.1 mmol) followed by afew drops of DMF. The reaction was stirred at rt for 1 h. Finalconcentration of 2-cyanoacetyl chloride was 0.4 M assuming completeconversion. To a solution of Intermediate 14H (4 mg, 8.4 μmol) andpyridine (2.0 μL, 0.025 mmol) in CH₂Cl₂ (100 μL) at 0° C. was added thefreshly prepared 0.4 M 2-cyanoacetyl chloride in CH₂Cl₂ (0.032 mL, 0.013mmol). The reaction was warmed to rt and stirred for 16 h. The reactionwas quenched with one drop of MeOH, diluted with EtOAc and washed with1:1 sat'd aq NaCl and water, dried over MgSO₄, filtered and concentratedto provide Intermediate 14I (7 mg, 153%), which was used in the nextstep without further purification. LCMS Anal. Calc'd for C₂₆H₂₄F₆N₂O₄542.47, found [M+H] 543.3.

Example 14

To a solution of Intermediate 14I (7 mg, 0.013 mmol) in EtOH (2 mL) wasadded 25% w/w sodium methoxide (0.015 mL, 0.065 mmol). The reaction wasstirred at rt for 1.5 h. The reaction was made acidic with a few dropsof 1 N aqueous HCl and then concentrated. The product was isolated bypreparative HPLC (MeOH/H₂OTFA). The fraction containing the product wasreduced in volume in vacuo, made basic with sat'd aq NaHCO₃ andextracted with EtOAc. The combined organic extracts were washed withsat'd aq NaCl, dried over MgSO₄, filtered and concentrated to provideExample 14 (2.9 mg, 42%). LCMS Anal. Calc'd for C₂₆H₂₂F₆N₂O₃ 524.46,found [M+H] 525.2. ¹H NMR (500 MHz, CD₃OD) δ 0.65 (t, J=8.80 Hz, 2H),1.18-1.25 (m, 2H), 1.99-2.08 (m, 2H), 2.31-2.43 (m, 2H), 3.85 (s, 3H),4.09 (t, J=6.05 Hz, 2H), 7.03 (d, J=8.80 Hz, 2H), 7.06 (br. s., 2H),7.23 (br. s., 2H), 7.58 (d, J=9.35 Hz, 2H).

Examples 15-1 and Example 15-2.3-Fluoro-4-(4-methoxyphenyl)-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,3,6-tetrahydropyridine-3-carbonitrile

To a solution of the Example 77 (70 mg, 0.140 mmol) in DMF (1.4 mL) wasadded Na₂CO₃ (30 mg, 0.28 mmol) followed by1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octane-bis-(tetrafluoroborate)(196 mg, 0.28 mmol). The reaction was heated to 80° C. overnight. Thereaction was cooled to rt and diluted with EtOAc and water. The layerswere separated and the aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with sat'd aq NaCl, dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified bypreparative HPLC (MeOH/H₂OTFA) to yield the product (44 mg, 61%) as amixture of two diastereoisomers. The two diastereoisomers were separatedby preparative chiral SFC method B to provide Example 15-1 (14.6 mg,20%) and Example 15-2 (17.2 mg, 23%). Data for Example 15-1: LCMS Anal.Calc'd for C₂₄H₁₉F₇N₂O₃ 516.41, found [M+H] 517.2. ¹H NMR (500 MHz,CD₃OD) δ 2.00-2.08 (m, 2H), 2.32-2.44 (m, 2H), 3.85 (s, 3H), 4.10 (t,J=6.05 Hz, 2H), 6.92 (d, J=1.10 Hz, 1H), 7.02 (d, J=8.80 Hz, 2H), 7.07(d, J=9.35 Hz, 2H), 7.50 (d, J=8.25 Hz, 2H), 7.57 (d, J=8.80 Hz, 2H).Analytical chiral HPLC method B: RT=3.23 min, 99% ee. Data for Example15-2: LCMS Anal. Calc'd for C₂₄H₁₉F₇N₂O₃ 516.41, found [M+H] 517.2. ¹HNMR (500 MHz, CD₃OD) δ 2.00-2.08 (m, 2H), 2.32-2.44 (m, 2H), 3.85 (s,3H), 4.10 (t, J=6.05 Hz, 2H), 6.92 (d, J=1.10 Hz, 1H), 7.02 (d, J=8.80Hz, 2H), 7.07 (d, J=9.35 Hz, 2H), 7.50 (d, J=8.25 Hz, 2H), 7.57 (d,J=8.80 Hz, 2H). Analytical chiral HPLC method B: RT=4.84 min, 99% ee.

Examples 15-3 and Example 15-4.3-Fluoro-4-(4-methoxyphenyl)-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,3,6-tetrahydropyridine-3-carbonitrile

Application of the method described for Example 15-1 and Example 15-2provided Example 15-3 (4.6 mg, 43%) and Example 15-4 (4.6 mg, 43%) fromthe R-isomer of Example 65 (10 mg, 0.02 mmol). Data for Example 15-3:LCMS Anal. Calc'd for C₂₄H₁₉F₇N₂O₃ 516.41, found [M+H] 517.1. ¹H NMR(500 MHz, CD₃OD) δ 2.00-2.08 (m, 2H) 2.31-2.44 (m, 2H) 3.85 (s, 3H) 4.10(t, J=6.05 Hz, 2H) 6.92 (d, J=1.65 Hz, 1H) 7.02 (d, J=8.80 Hz, 2H) 7.07(d, J=8.80 Hz, 2H) 7.50 (d, J=8.25 Hz, 2H) 7.57 (d, J=8.80 Hz, 2H).Analytical chiral HPLC method B: RT=5.13 min, 99% ee. Data for Example15-4: LCMS Anal. Calc'd for C₂₄H₁₉F₇N₂O₃ 516.41, found [M+H] 517.1. ¹HNMR (500 MHz, CD₃OD) δ 1.99-2.07 (m, 2H) 2.30-2.43 (m, 2H) 3.84 (s, 3H)4.09 (t, J=6.05 Hz, 2H) 6.78 (s, 1H) 7.02 (d, J=8.80 Hz, 2H) 7.05 (d,J=9.35 Hz, 2H) 7.54 (dd, J=8.25, 4.95 Hz, 4H). Analytical chiral HPLCmethod B: RT=5.13 min, 99% ee.

Example 16-1 and Example 16-2.N-(4-Methoxyphenyl)-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)piperidine-3-carboxamide

To a solution of Example 6-2 (90 mg, 0.15 mol) in MeOH (2 mL) was added10% palladium on carbon (5 mg). The mixture was stirred under hydrogen(50 psi) overnight. Additional palladium on carbon (5 mg) was added andthe reaction was stirred under hydrogen (50 psi) for an additional 1 h.The catalyst was removed by filtration through a pad of Celite® and thesolution was concentrated in vacuo. The products were partly separatedby preparative HPLC (CH₃CN/H₂O/TFA). Fractions containing the twoproducts were combined and separated by chiral HPLC method D to provideExample 16-1 and Example 16-2. Data for Example 16-1: LCMS Anal. Calc'dfor C₃₁H₃₀F₆N₂O₄ 608.57, found [M+H] 609.2. ¹H NMR (400 MHz, CD₃OD) δ1.97-2.14 (m, 2H), 2.25 (s, 3H), 2.32-2.46 (m, 2H), 2.54-2.69 (m, 2H),3.17 (td, J=11.82, 3.85 Hz, 1H), 3.60 (d, J=11.54 Hz, 1H), 3.71 (s, 3H),4.10 (t, J=6.05 Hz, 2H), 6.76 (d, J=8.79 Hz, 2H), 6.99-7.12 (m, 6H),7.13-7.23 (m, 2H), 7.55 (d, J=8.79 Hz, 2H). Analytical chiral HPLCmethod D RT=6.75 min, 99% ee. Data for Example 16-2: LCMS Anal. Calc'dfor C₃₁H₃₀F₆N₂O₄ 608.57, found [M+H] 609.2. ¹H NMR (400 MHz, CD₃OD) δ7.52 (d, J=8.8 Hz, 2H), 7.25-7.20 (m, 2H), 7.19-7.15 (m, 2H), 7.14-7.10(m, 2H), 7.02-6.97 (m, 2H), 6.81-6.75 (m, 2H), 4.07 (t, J=6.0 Hz, 2H),3.94-3.84 (m, 1H), 3.73 (s, 3H), 3.60 (d, J=12.1 Hz, 1H), 2.90 (dd,J=14.8, 3.3 Hz, 1H), 2.45-2.32 (m, 2H), 2.31 (dd, 1H, overlaps with peakat δ□ 2.27), 2.27 (s, 3H), 2.08-1.98 (m, 2H). Preparative chiral HPLCmethod D: RT=10.9 min, 99% ee.

Examples 17-101 expressed by Formula (IIa), unless noted in the table,may be made by one skilled in the art by appropriate application of theprocedures described for Examples 1-16. R¹¹ to R¹⁵ are hydrogen, unlessnoted in the table.

TABLE 2 (IIa)

Example R¹ R² R⁶ R¹¹-R¹⁵ [M + H] ¹HNMR (400 MHz, MeOD) 17 Rac

CH₃ CN R¹³ = morpholine 459.2* 18 Rac

CH₃ CN R¹² = CH₃ R¹³ = CH₃ 345.1* 19 Rac

CH₃ CN R¹³ = OCH₂CH₃ 377.2* 20 Rac

CH₃ CN R¹³ = t-Bu 401.2* 21 Rac

CH₃

R¹³ = CH₃ 360.2 22 Rac

CF₃ CN R¹³ = CH₃ 371.2 23 Rac

CH₃ CN R¹³ = CH₃ 331.3 24 Rac

CF₃ CN R¹³ = CH₃ 391.1 25 Rac

CF₃ CN R¹³ = CH₃ 375.2 26 Rac

CF₃ CN R¹³ = CH₃ 393.2 27 Rac

CF₃ CN R¹³ = CH₃ 375.2 28 Rac

CF₃ CN R¹³ = CH₃ 413.3 29 Rac

CF₃ CN R¹² = CH₃ 387.2 30 Rac

CF₃ CN R¹³ = CH₃ 387.2 31 Rac

CF₃ CN R¹³ = CH₃ 400.2 32 Rac

CF₃ CN R¹³ = CH₃ 435.2 33 Rac

CF₃ CN R¹³ = CH₃ 483.3 2.03-2.12 (m, 2 H) 2.25- 2.36 (m, 2 H) 2.42 (s, 3H) 3.51-3.68 (m, 2 H) 4.04 (t, J = 5.50 Hz, 2 H) 6.94 (d, J = 8.80 Hz, 2H) 7.31 (d, J = 7.70 Hz, 2 H) 7.40 (d, J = 8.80 Hz, 2 H) 7.47 (d, J =7.70 Hz, 2 H) 7.64 (br. s., 1 H). 34 Rac

CF₃ CN R¹³ = CH₃ 471.4 [M − H]− 35 Rac

CF₃ CN R¹³ = CH₃ 491.3 2.06-2.18 (m, 2 H) 2.41 (s, 3 H) 2.81 (t, J =7.70 Hz, 2 H) 3.45-3.68 (m, 2 H) 3.97 (t, J = 6.32 Hz, 2 H) 6.55 (s, 1H) 6.93 (d, J = 8.80 Hz, 2 H) 7.21 (d, J = 7.15 Hz, 3 H) 7.25-7.31 (m, 4H) 7.37 (d, J = 8.25 Hz, 2 H) 7.45 (d, J = 8.25 Hz, 2 H). 36 Rac

CF₃ CN R¹³ = CH₃ 469.3 1.16 (dd, J = 12.10, 8.25 Hz, 2 H) 1.54 (dd, J =7.42, 4.67 Hz, 2 H) 1.60-1.70 (m, 2 H) 1.81 (q, J = 6.60 Hz, 4 H) 1.96(m, J = 7.70 Hz, 1 H) 2.41 (s, 3 H) 3.45-3.64 (m, 2 H) 3.98 (t, J = 6.60Hz, 2 H) 6.50 (s, 1 H) 6.94 (d, J = 9.35 Hz, 2 H) 7.23-7.32 (m, 2 H)7.37 (d, J = 8.80 Hz, 2 H) 7.44 (d, J = 8.25 Hz, 2 H). 37 Rac

CF₃ CN R¹³ = CH₃ 443.3 38 Rac

CF₃

R¹³ = CH₃ 430.1 39 S-isomer

CF₃ CN R¹³ = CH₃ 387.2 40 Rac

CF₃ CN R¹³ = CH₃ 463.2 41 Rac

CF₃

R¹³ = CH₃ 499.2 42 Rac

CF₃ CN R¹³ = CH₃ 427.4 0.85-0.96 (m, 3 H) 1.33 (d, J = 2.75 Hz, 4 H)1.47-1.69 (m, 4 H) 2.41 (s, 3 H) 2.56- 2.67 (m, 2 H) 3.45-3.66 (m, 2 H)6.46 (br. s., 1 H) 7.20- 7.31 (m, 4 H) 7.37 (d, J = 7.15 Hz, 2 H) 7.45(d, J = 6.60 Hz, 2 H). 43 Rac

CF₃ CN R¹³ = CH₃ 434.3 44 Rac

CF₃ CN R¹³ = CH₃ 450.3 45 Rac

CF₃ CN R¹³ = CH₃ 449.3 46 Rac

CF₃ CN R¹³ = CH₃ 451.3 47 Rac

CF₃ CN R¹³ = CH₃ 463.3 48 Rac

CF₃

R¹³ = CH₃ 561.4 2.36 (s, 3 H) 3.40-3.59 (m, 2 H) 6.82 (s, 1 H) 6.93 (t,J = 8.79 Hz, 2 H) 7.01-7.13 (m, 5 H) 7.15-7.20 (m, 3 H) 7.34-7.45 (m, 4H) 7.48 (d, J= 8.79 Hz, 2 H) 9.86 (s, 1 H). 49 Rac

CF₃

R¹³ = CH₃ 547.4 2.30 (s, 3 H) 3.57-3.81 (m, 2 H) 6.96 (t, J = 8.79 Hz, 2H) 7.17 (d, J = 7.70 Hz, 2 H) 7.27-7.38 (m, 4 H) 7.83 (m, 4 H) 9.11 (s,2 H) 9.16 (s, 1 H) 50 Rac

CF₃

R¹³ = CH₃ 547.4 51 Rac

CF₃

R¹³ = CH₃ 539.5 0.90 (t, J = 6.87 Hz, 3 H) 1.28-1.40 (m, 4 H) 1.58- 1.71(m, 2 H) 2.35 (s, 3 H) 2.55-2.71 (m, 2 H) 3.30- 3.60 (m, 2 H) 6.63 (s, 1H) 6.92 (t, J = 8.52 Hz, 2 H) 7.05-7.12 (m, 2 H) 7.14- 7.20 (m, 2 H)7.22-7.31 (m, 2 H) 7.37-7.49 (m, 4 H) 9.94 (s, 1 H). 52 Rac

CF₃

R¹³ = CH₃ 563.4 53 S-isomer

CF₃ CN R¹³ = CH₃ 483.2 1.93-2.09 (m, 2 H) 2.27- 2.38 (m, 2 H) 2.40 (s, 3H) 3.62-3.78 (m, 2 H) 4.06 (t, J = 6.05 Hz, 2 H) 7.00 (d, J = 8.80 Hz, 2H) 7.33 (d, J = 7.70 Hz, 2 H) 7.44-7.58 (m, 4 H). 54 Rac

CF₃

R¹³ = CH₃ 575.3 55 Rac

CF₃

R¹³ = CH₃ 571.4 56 Rac

CF₃

R¹³ = CH₃ 591.3 57 Rac

CF₃

R¹³ = CH₃ 605.4 2.02 (dd, J = 9.90, 6.05 Hz, 2 H) 2.28-2.40 (m, 5 H)2.45- 2.58 (m, 2 H) 3.12-3.35 (m, 2 H) 3.37-3.60 (m, 2 H) 4.05 (t, J =6.05 Hz, 2 H) 6.91-7.01 (m, 4 H) 7.09- 7.20 (m, 5 H) 7.21-7.26 (m, 2 H)7.50 (d, J = 8.80 Hz, 2 H). 58 Rac

CF₃

R¹³ = CH₃ 607.3 1.96-2.07 (m, 2 H) 2.26- 2.32 (m, 3 H) 2.32-2.42 (m, 2H)3.45-3.67 (m, 2 H) 4.06 (t, J = 6.05 Hz, 2 H) 6.61 (dd, J = 8.25, 2.20Hz, 1 H) 6.83 (d, J = 8.25 Hz, 1 H) 6.98 (d, J = 8.80 Hz, 2 H) 7.03 (s,1 H) 7.09 (t, J = 8.25 Hz, 1 H) 7.16 (d, J = 8.25 Hz, 2 H) 7.28 (d, J =8.25 Hz, 2 H) 7.52 (d, J = 8.80 Hz, 2 H). 59 Rac

CF₃

R¹³ = CH₃ 577.3 1.95-2.08 (m, 2 H) 2.28 (s, 3 H) 2.32-2.42 (m, 2 H)3.42- 3.70 (m, 2 H) 4.05 (t, J = 6.05 Hz, 2 H) 6.97 (d, J= 8.80 Hz, 2 H)7.00-7.06 (m, 1 H) 7.15 (d, J= 8.25 Hz, 2 H) 7.20 (t, J = 7.97 Hz, 2H)7.30 (dd, J = 16.77, 7.97 Hz, 4 H) 7.52 (d, J = 8.80 Hz, 2 H). 60 Rac

CF₃

R¹³ = CH₃ 611.3 61 Rac

CF₃

R¹³ = CH₃ 611.3 62 Rac

CF₃

R¹³ = CH₃ 611.3 63 Rac

CF₃ CN R¹³ = CH₃ 469.1 2.40 (s, 3 H) 2.63-2.75 (m, 2 H) 3.65-3.77 (m, 2H) 4.24 (t, J = 6.05 Hz, 2 H) 7.01 (d, J = 9.35 Hz, 2H) 7.33 (d, J =7.70 Hz, 2 H) 7.50 (d, J = 8.25 Hz, 2 H) 7.54 (d, J = 8.80 Hz, 2 H). 64Rac

CF₃ CN R¹² = OCH₃ 499.2 65 Rac

CF₃ CN R¹³ = OCH₃ 499.2 1.95-2.07 (m, 2 H) 2.29- 2.43 (m, 2 H) 3.88 (s,3 H) 3.92 (d, J = 16.51 Hz, 1 H) 4.06 (t, J = 6.05 Hz, 2 H) 4.55 (d, J =16.23 Hz, 1 H) 6.96 (d, J = 9.08 Hz, 2 H) 7.01 (d, J = 8.80 Hz, 2 H)7.52 (d, J = 9.08 Hz, 2 H) 7.97 (d, J = 9.08 Hz, 2 H) 66 Rac

CF₃ CN R¹³ = CN 494.2 67 Rac

CF₃ CN R¹¹ = F 487.2 68 Rac

CF₃ CN R¹² = Cl 503.2 69 Rac

CF₃ CN R¹² = CN 494.2 70 Rac

CF₃ H R¹³ = CH₃ 458.2 71 Rac

CF₃ CN all H 469.2 72 Rac

CF₃ CN R¹³ = Cl 503.1 73 Rac

CF₃ CN

519.2 8.15 (d, J = 1.7 Hz, 1 H), 8.01- 7.95 (m, 2 H), 7.92 (d, J= 8.0Hz, 1H), 7.65-7.55 (m, 5H), 7.05-7.00 (m, 2H), 4.07 (t, J= 6.1 Hz, 2H),3.85 (ABq, J = 18.1 Hz, 2H), 2.42- 2.29 (m, 2H), 2.06-1.98 (m, 2H) 74Rac

CF₃ CN R¹³ = F 487.2 75 Rac

CF₃ CN R¹³ = CF₃ 537.2 76 Rac

CF₃ CN R¹² = CH₃ 483.2 77 S-isomer

CF₃ CN R¹³ = OCH₃ 499.2 1.97-2.06 (m, 2 H) 2.27- 2.42 (m, 2 H) 3.66 (d,J = 17.90 Hz, 1 H) 3.75 (d, J = 17.90 Hz, 1 H) 3.87 (s, 3 H) 4.06 (t, J= 6.05 Hz, 2 H) 6.96-7.02 (m, 1 H) 7.03- 7.08 (m, 2 H) 7.52 (d, J = 8.80Hz, 2 H) 7.61-7.68 (m, 2 H) 78 Rac

CF₃ CN R¹³ = OCHF₂ 535.1 7.69-7.63 (m, 2H), 7.54 (d, J = 9.1 Hz, 2H),7.31-7.25 (m, 2H), 7.01 (m, 2H), 6.96 (t, J = 73.5 Hz, 1 H), 4.07 (t, J= 6.1 Hz, 2H), 3.78-3.67 (m, 2H), 2.44-2.30 (m, 2H), 2.07-1.97 (m, 2H)79 Rac

CF₃ CN R¹³ = OCF₃ 553.1 80 Rac

CF₃ CN R¹³ = OCH₂CH₃ 513.2 81 Rac

CF₃ CN R₁₁ = F R¹³= OCH₃ 517.2 7.51 (d, J= 9.1 Hz, 2H), 7.36- (t, J =8.8 Hz, 1H), 7.04- 6.97 (m, 2H), 6.91-6.83 (m, 2H), 4.08 (t, J = 6.1 Hz,2H), 3.87 (s, 3H), 3.65 (s, 2 H), 2.46-2.29 (m, 2H), 2.08- 1.98 (m, 2H)82 Rac

CF₃

R¹³ = CH₃ 591.2 7.52 (d, J= 8.8 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.15(d, J= 7.7 Hz, 2H), 7.19 (d, J= 8.8 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H),6.98 (d, J= 7.7 Hz, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.64 (d, J = 17.0 Hz,1H), 3.48 (d, J= 17.0 Hz, 1H), 2.39-2.32 (m, 2H), 2.29 (s, 3H), 2.24 (s,3H), 2.06-1.98 (m, 2H). 83 Rac

CF₃

R¹³ = CH₃ 661.2 7.53 (d, J = 8.8 Hz, 2H), 7.46- 7.41 (m, 2H), 7.31-7.24(m, J = 8.2 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 7.7 Hz, 2H),7.01-6.96 (m, 2H), 4.07 (t, J = 6.0 Hz, 2H), 3.65 (d, J = 17.0 Hz, 1H),3.50 (d, J = 17.0 Hz, 1H), 2.43-2.33 (m, 2H), 2.30 (s, 3H), 2.07-1.99(m, 2H). 84 Rac

CF₃

R¹³ = CH₃ 625.2 7.52 (d, J= 8.8 Hz, 2H), 7.30- 7.24 (m, 3H), 7.17 (d, J= 7.7 Hz, 2H), 7.01-6.90 (m, 4H), 4.06 (t, J = 6.0 Hz, 2H), 3.82-3.77(s, 3H), 3.64 (d, J = 17.0 Hz, 1H), 3.49 (d, J = 17.0 Hz, 1H), 2.42-2.33(m, 2H), 2.30 (s, 3H), 2.08-1.96 (m, 2H). 85 Rac

CF₃

R¹³ = CH₃ 609.2 7.56-7.50 (ab quartet, J = 9.3 Hz, 2H), 7.30-7.20 (m,3H), 7.16 (d, J = 8.2 Hz, 2H), 7.05 (t, J = 8.2 Hz, 1H), 7.01- 6.95 (m,J = 8.8 Hz, 2H), 6.91 (dd, J = 8.2, 1.6 Hz, 1H), 4.07 (t, J = 6.0 Hz,2H), 3.64 (d, J= 17.6 Hz, 1H), 3.49 (d, J = 17.0 Hz, 1H), 2.43-2.32 (m,2H), 2.30 (s, 3H), 2.16 (s, 3H), 2.08-1.97 (m, 2H). 86 Rac

CF₃

R¹³ = CH₃ 645.2 7.58-7.48 (m, 6H), 7.27 (d, J = 8.2 Hz, 2H), 7.15 (d, J= 8.2 Hz, 2H), 7.00-6.95 (m, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.65 (d, J =17.6 Hz, 1H), 3.50 (d, J = 17.0 Hz, 1H), 2.43-2.31 (m, 2H), 2.28 (s,3H), 2.09-1.95 (m, 2H). 87 Rac S-isomer

CF₃

R¹³ = CH₃ 538.2 88 Rac

CF₃

R¹³ = CH₃ 579.2 2.31 (s, 3 H) 3.45-3.69 (m, 2 H) 3.70-3.76 (s, 3 H) 4.56(q, J = 8.25 Hz, 2 H) 6.78 (d, J = 9.35 Hz, 2 H) 7.07 (d, J = 9.35 Hz, 2H) 7.13-7.22 (m, 4 H) 7.29 (d, J = 8.25 Hz, 2 H) 7.59 (d, J = 8.80 Hz, 2H). 89 Rac

CF₃ CN R¹³ = CH₃ 455.1 90 Rac

CF₃

R¹³ = CH₃ 498.1 2.28 (s, 3 H) 3.63-3.82 (m, 2 H) 4.58 (q, J = 8.61 Hz, 2H) 6.88 (d, J= 8.25 Hz, 2 H) 7.10 (dd, J = 12.65, 8.80 Hz, 4 H) 7.65 (d,J = 8.80 Hz, 2 H). 91 S-isomer

CF₃ CN R₁₁ = F R¹³ = OCH₃ 517.2 7.51 (d, J = 9.1 Hz, 2H), 7.36 (t, J =8.8 Hz, 1H), 7.03- 6.99 (m, 2H), 6.90-6.84 (m, 2H), 5.49 (s, 1H), 4.08(t, J = 6.1 Hz, 2H), 3.87 (s, 3H), 3.65 (s, 2H), 2.46-2.28 (m, 2H),2.10-1.97 (m, 2H) 92 Rac

CF₃

R¹³ = OCH₂CH₃ 556.3 1.34 (t, J = 6.87 Hz, 3 H) 1.96-2.09 (m, 2 H) 2.26-2.43 (m, 2 H) 3.70 (s, 2 H) 3.98 (q, J = 6.78 Hz, 2 H) 4.06 (t, J = 6.05Hz, 2 H) 6.78 (d, J = 8.80 Hz, 2 H) 6.92 (d, J = 8.80 Hz, 2 H) 7.01 (d,J = 8.80 Hz, 2 H) 7.58 (d, J = 8.80 Hz, 2 H). 93 Rac

CF₃

R¹³ = OCHF₂ 578.3 1.96-2.12 (m, 2 H) 2.28- 2.45 (m, 2 H) 3.63-3.85 (m, 2H) 4.07 (t, J = 6.05 Hz, 2 H) 6.95-7.08 (m, 7 H) 7.59 (d, J = 8.80 Hz, 2H). 94 S-isomer

CF₃

R¹³ = CH₃ 661.3 1.97-2.08 (m, 2 H) 2.29 (s, 3 H) 2.32-2.40 (m, 2 H) 3.50(d, J = 17.05 Hz, 1 H) 3.65 (d, J = 17.60 Hz, 1 H) 4.06 (t, J = 6.05 Hz,2 H) 6.98 (d, J = 8.80 Hz, 2 H) 7.14 (dd, J = 16.77, 8.52 Hz, 4 H) 7.28(d, J = 8.25 Hz, 2 H) 7.43 (d, J = 9.35 Hz, 2 H) 7.52 (d, J = 8.80 Hz, 2H). 95 S-isomer

CF₃

R¹¹ = F R¹³ = OCH₃ 560.3 1.95-2.08 (m, 2 H) 2.28- 2.42 (m, 2 H)3.58-3.71 (m, 2 H) 3.76 (s, 3 H) 4.06 (t, J = 6.05 Hz, 2 H) 6.59 (dd, J= 12.92, 2.47 Hz, 1 H) 6.69 (dd, J = 8.80, 2.75 Hz, 1 H) 6.91-6.96 (m, 1H) 7.00 (d, J = 8.80 Hz, 2 H) 7.57 (d, J = 8.80 Hz, 2 H). 96 Rac

CF₃

R¹² = CH₃ 526.3 97 Rac

CF₃

All H 512.2 98 Rac

CF₃

R¹³ = CF₃ 580.3 7.60 (t, J = 8.2 Hz, 4H), 7.18 (d, J = 8.2 Hz, 2H), 7.03(d, J = 8.8 Hz, 2H), 4.08 (t, J = 6.0 Hz, 2H), 3.80 (d, J = 18.1 Hz,1H), 3.69 (d, J = 18.1 Hz, 1H), 2.45-2.31 (m, 2H), 2.11-1.93 (m, 2H). 99Rac

CF₃

R¹² = Cl 546.2 100 Rac

CF₃

R¹² = OCH₃ 542.3 101 Rac

CF₃

R¹³ = Cl 546.2 *Data reported as molecular weight of compound based onelectrospray mass spec results

Example 102.N⁵-(4-Methoxyphenyl)-2-methyl-6-oxo-4-p-tolyl-N²-(4,4,4-trifluorobutyl)-1,2,3,6-tetrahydropyridine-2,5-dicarboxamide

Intermediate 102A. (E)-Ethyl 2-methyl-4-oxo-4-p-tolylbut-2-enoate

A solution of Intermediate 2D (3.02 g, 7.65 mmol) and ethyl2-oxopropanoate (0.74 g, 6.37 mmol) in THF (12 mL) in a 5 mL microwavevial equipped with a magnetic stirrer was heated at 150° C. undermicrowave conditions for 20 min. The solvent was removed under vacuumand the residue was purified by silica gel chromatography (80 g silicagel, eluted with EtOAc in hexanes) to provide the desired product (1.067g, 72%) as a yellow oil. LCMS Anal. Calc'd for C₁₄H₁₆O₃ 232.11, found[M+H] 233.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.87 (d, J=8.25 Hz, 2H), 7.69(q, J=1.56 Hz, 1H), 7.28 (d, J=7.98 Hz, 2H), 4.30 (q, J=7.15 Hz, 2H),2.42 (s, 3H), 2.16 (d, J=1.38 Hz, 3H), 1.36 (t, J=7.02 Hz, 3H).

Intermediate 102B. Ethyl 2-amino-2-methyl-4-oxo-4-p-tolylbutanoate

To a solution of Intermediate 102A (1.067 g, 4.59 mmol) in DMSO (20 mL)under argon was added NH₄OH (18.04 mL, 271 mmol) and the reactionmixture was stirred at rt overnight. The reaction mixture was dilutedwith EtOAc (75 mL) and washed sequentially with water (40 mL) and brine(20 mL). The organic phase was dried over MgSO₄ and concentrated invacuo to give a yellow oil. The oil was purified by silica gelchromatography (120 g silica gel) to provide the desired product (0.632g, 55%) as a clear oil. LCMS Anal. Calc'd for C₁₄H₁₉NO₃ 249.14, found[M+H] 250.1. ¹H NMR (500 MHz, CDCl₃) δ 7.83 (d, J=8.25 Hz, 2H), 7.24 (d,J=7.98 Hz, 2H), 4.14 (dd, J=7.15, 2.75 Hz, 2H), 3.65 (d, J=17.61 Hz,1H), 3.20 (d, J=17.61 Hz, 1H), 2.40 (s, 3H), 2.18-2.27 (m, 2H), 1.39 (s,3H), 1.19 (t, J=7.01 Hz, 3H).

Intermediate 102C. Ethyl2-(3-(4-methoxyphenylamino)-3-oxopropanamido)-2-methyl-4-oxo-4-p-tolylbutanoate

To a solution of Intermediate 6B (0.388 g, 1.855 mmol) in DCM (10 mL)under argon was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.293g, 2.192 mmol) and the reaction mixtrue was stirred at rt for 20 min Asolution of Intermediate 102B (0.4204 g, 1.686 mmol) in DCM (1.000 mL)followed by pyridine (0.409 mL, 5.06 mmol) were added and the reactionmixture was stirred at rt for 2.5 h. The reaction mixture wasconcentrated to give a dark oil which was dissolved in EtOAc (15 mL) andwashed with water (5 mL). The organic phase was dried over MgSO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (80 g silica gel) to provide the desired product (0.650g, 88%) as an orange oil. LCMS Anal. Calc'd for C₂₄H₂₈N₂O₆ 440.19, found[M+H] 441.2. ¹H NMR (500 MHz, CDCl₃) δ 7.83 (d, J=8.25 Hz, 2H), 7.24 (d,J=7.98 Hz, 2H), 4.14 (dd, J=7.15, 2.75 Hz, 2H), 3.65 (d, J=17.61 Hz,1H), 3.20 (d, J=17.61 Hz, 1H), 2.40 (s, 3H), 2.18-2.27 (m, 2H), 1.39 (s,3H), 1.19 (t, J=7.01 Hz, 3H).

Intermediate 102D,5-(4-Methoxyphenylcarbamoyl)-2-methyl-6-oxo-4-p-tolyl-1,2,3,6-tetrahydropyridine-2-carboxylicacid

To a solution of Intermediate 102C (0.033 g, 0.075 mmol) in THF (8 mL)and water (1.600 mL) was added lithium hydroxide monohydrate (3.77 mg,0.090 mmol) and the reaction mixture was stirred at rt for 1 h. Thereaction mixture was acidified with AcOH (5 drops) and diluted withEtOAc (10 mL) and water (3 mL). The phases were separated and theaqueous phase was extracted with EtOAc (10 mL). The organic phases werecombined and dried over MgSO₄, filtered, and concentrated in vacuo togive the desired product (0.0213 g, 72%) as a white solid. LCMS Anal.Calc'd for C₂₂H₂₂N₂O₅ 394.15, found [M+H] 395.0.

Example 102

To a solution of Intermediate 102D (0.0213 g, 0.054 mmol) in DCM (2 mL)under argon was added EDC (0.014 g, 0.076 mmol), HOBT (9.92 mg, 0.065mmol), 4,4,4-trifluorobutan-1-amine (8.24 mg, 0.065 mmol), and DIEA(0.019 mL, 0.108 mmol). The reaction mixture was stirred at rt for 3days. The reaction mixture was diluted with EtOAc (5 mL) and thesolution was washed with water (2 mL) and brine (2 mL). The organicphase was dried over MgSO₄, filtered, and concentrated in vacuo to givean orange solid which was purified by preparative HPLC (ACN/H₂O/TFA) toafford the desired product (4.6 mg, 15%) as a pale yellow solid. LCMSAnal. Calc'd for C₂₆H₂₈F₃N₃O₄ 503.2, found [M+H] 504.1. ¹H NMR (500 MHz,CDCl₃) δ 8.46 (br. s., 1H), 7.61 (br. s., 1H), 7.24-7.32 (m, 4H), 7.16(d, J=7.83 Hz, 2H), 6.79 (d, J=8.84 Hz, 2H), 3.75 (s, 3H), 3.56 (d,J=17.18 Hz, 1H), 3.22-3.37 (m, 2H), 3.14 (br. s., 1H), 2.73 (d, J=17.18Hz, 1H), 2.34 (s, 3H), 2.00-2.15 (m, 2H), 1.70-1.80 (m, 2H), 1.54 (s,3H).

Example 103.N-(4-Cyanophenyl)-5,5-difluoro-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxamide

Intermediate 103A. Methyl2,2-difluoro-3-oxo-3-(4-(4,4,4-trifluorobutoxy)phenyl)propanoate

To a solution of Intermediate 14A (3 g, 9.86 mmol) and selectFluor(10.48 g, 29.6 mmol) in acetonitrile (10 mL) was added 1 M methanolictetrabutylammonium hydroxide (19.72 mL, 19.72 mmol). The reactionmixture was heated to 82° C. for 10 min under microwave conditions. Thereaction was diluted with 1:1 ACN and MeOH and filtered rinsing with 1:1ACN in MeOH (50 mL). The filtrate was evaporated to dryness and thecrude product was purified by silica gel chromatography (80 g silicagel, elute with EtOAc in hexanes) to yield the desired product (2.34 g,69%) as a clear, colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 8.08 (d,J=9.08 Hz, 2H), 6.98 (d, J=9.08 Hz, 2H), 4.13 (t, J=6.05 Hz, 2H), 3.93(s, 3H), 2.27-2.39 (m, 2H), 2.07-2.15 (m, 2H).

Intermediate 103B.2,2-Difluoro-1-(piperidin-1-yl)-3-(4-(4,4,4-trifluorobutoxy)phenyl)propane-1,3-dione

Piperidine (175 μL, 1.763 mmol) was slowly added to Intermediate 103A(500 mg, 1.470 mmol) at rt. The reaction was stirred at rt for 3 h. Thereaction was diluted with CH₂Cl₂, loaded onto a 12 g SiO₂ column andeluted with EtOAc in hexanes. Fractions containing the product werecombined and evaporated to dryness to provide the product (520 mg, 81%)as a clear oil. LCMS Anal. Calc'd for C₁₈H₂₀F₅NO₃ 393.14, found [M+H]394.2. ¹H NMR (500 MHz, CDCl₃) δ 8.10 (d, J=9.1 Hz, 2H), 6.98-6.91 (m,2H), 4.10 (t, J=5.9 Hz, 2H), 3.61-3.56 (m, 2H), 3.54-3.50 (m, 2H),2.39-2.26 (m, 2H), 2.14-2.05 (m, 2H), 1.69-1.61 (m, 2H), 1.60-1.51 (m,4H).

Intermediate 103C.N-(2,2-Difluoro-3-oxo-3-(piperidin-1-yl)-1-(4-(4,4,4-trifluorobutoxy)phenyl)propylidene)-2-methylpropane-2-sulfinamide

To a solution of Intermediate 103B (1.97 g, 5.01 mmol) and2-methylpropane-2-sulfinamide (1.821 g, 15.02 mmol) in anhydrous THF(25.04 mL) was added Ti(OEt)₄ (5.19 mL, 25.04 mmol). The reaction washeated at refluxed temperature overnight. The reaction was cooled to rt,poured into brine, diluted with EtOAc, and stirred for 30 min. Thetitanium oxide was removed by filtering through a plug of Celite®. Thefiltrate layers were separated and the organic layer was washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography (80 g silica gel, eluted withEtOAc in hexanes to yield the desired product (1.62 g, 59%) as a yellowoil. ¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, J=8.80 Hz, 2H), 6.95 (d, J=9.08Hz, 2H), 4.07 (t, J=6.05 Hz, 2H), 3.62-3.69 (m, 1H), 3.52-3.58 (m, 1H),3.39 (t, J=5.09 Hz, 2H), 2.26-2.37 (m, 2H), 2.05-2.11 (m, 2H), 1.53-1.70(m, 7H), 1.25 (s, 9H).

Intermediate 103D.2-Methyl-N-(1,1,1,3,3-pentafluoro-4-oxo-4-(piperidin-1-yl)-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)propane-2-sulfinamide

To a solution of TBAT (3.43 g, 6.36 mmol) in DMF (5.89 mL) was added asolution of Intermediate 103C (1.17 g, 2.356 mmol) in THF (5.89 mL). Thesolution was cooled to 0° C., and then 2 M TMSCF₃ (3.53 mL, 7.07 mmol)in THF was added dropwise. The reaction was stirred at 0° C. for 1 h,and then quenched with brine (20 mL) at 0° C. The mixture was warmed tort and diluted with water and EtOAc. The layers were separated. Theaqueous layer was washed with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography (80 g silica gel,eluted with EtOAc in hexanes) to afford the desired product (773 mg,58%) as a yellow gum. LCMS Anal. Calc'd for C₂₃H₃₀F₈N₂O₃S 566.18, found[M+H] 567.1. ¹H NMR (500 MHz, CD₃OD) δ 7.69 (d, J=8.53 Hz, 2H), 6.91 (d,J=9.08 Hz, 2H), 4.03 (t, J=5.91 Hz, 2H), 3.50-3.62 (m, 2H), 3.34-3.45(m, 2H), 2.23-2.35 (m, 2H), 1.98-2.07 (m, 2H), 1.48-1.69 (m, 6H), 1.26(s, 9H).

Intermediate 103E.N-Benzyl-2-methyl-N-(1,1,1,3,3-pentafluoro-4-oxo-4-(piperidin-1-yl)-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)propane-2-sulfinamide

A solution of Intermediate 103D (461 mg, 0.814 mmol) in anhydrous DMF(0.5 mL) was added to a suspension of NaH (65 mg, 1.627 mmol) (60% inmineral oil) at 0° C. After stirring for 5 min, BnBr (0.484 mL, 4.07mmol) was added. The reaction mixture was warmed to rt and stirred for 1h. The reaction was diluted with EtOAc, washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (4 g silica gel, eluted with EtOAc in hexanes) toyield the desired product (260 mg, 44%) as a yellow gum. ¹H NMR (500MHz, CDCl₃) δ 7.75 (d, J=8.5 Hz, 2H), 7.33-7.27 (m, 3H), 7.14 (dd,J=7.3, 2.1 Hz, 2H), 6.80 (d, J=9.1 Hz, 2H), 4.46-4.38 (m, 2H), 4.00-3.95(m, 2H), 3.72 (br. s., 1H), 3.51 (br. s., 1H), 3.35-3.10 (m, 2H),2.37-2.25 (m, 2H), 2.09-1.99 (m, 2H), 1.70-1.39 (m, 6H), 1.34-1.29 (m,9H).

Intermediate 103F.2-Methyl-N-(1,1,1,3,3-pentafluoro-4-oxo-4-p-tolyl-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)propane-2-sulfinamide

Mg turnings were suspended in 0.1 N aq HCl for a few minutes, rinsedwith water, MeOH and dried under vacuum. A flame dried flask equippedwith a stir bar was charged with Mg turnings (0.243 g, 10 mmol),anhydrous THF (4.4 mL) and 4-bromotoluene (1.71 g, 10 mmol) in anhydrousTHF (4.4 mL) followed by several drops of 1,2-dibromoethane. Thereaction initiated in a few minutes and the mixture became warm. Theapproximate concentration of the Grignard reagent is 1 M. The mixturewas diluted with 10 mL anhydrous THF to produce a clear solution ofp-tolylmagnesium bromide (˜0.5 M). To a solution of Intermediate 103E(260 mg, 0.396 mmol) in THF (3959 μL) at 0° C. was added the freshlyprepared p-tolylmagnesium bromide (3959 μL, 1.980 mmol). The reactionwas warmed to rt, concentrated to half of the original volume, andstirred for 3 h. The reaction was cooled to 0° C., quenched with sat'daq NH₄Cl, and then diluted with EtOAc. The layers were separated and theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatography (24g silica gel, eluted with EtOAc in hexanes) to afford the desiredproduct (60 mg, 24%) as a yellow gum. ¹H NMR (500 MHz, CDCl₃) δ 7.73 (d,J=8.0 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.83 (d,J=8.8 Hz, 2H), 4.19 (s, 1H), 4.01 (br. s., 2H), 2.40 (s, 3H), 2.31 (dd,J=16.2, 10.2 Hz, 2H), 2.10-1.99 (m, 2H), 1.25 (s, 9H).

Intermediate 103G.3-Amino-2,2,4,4,4-pentafluoro-1-p-tolyl-3-(4-(4,4,4-trifluorobutoxy)phenyl)butan-1-one,HCl

To a solution of Intermediate 103F (30 mg, 0.052 mmol) in MeOH (0.5 mL)was added 4.0 M HCl (0.026 mL, 0.105 mmol) in dioxane. The reaction wasstirred at rt for 1 h. The reaction was concentrated and the crudeproduct was used in the next step without further purification. LCMSAnal. Calc'd for C₂₁H₁₉F₈NO₂ 469.13, found [M+H] 470.1.

Intermediate 103H. Ethyl5,5-difluoro-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxylate

Intermediate 103G (268 mg, 0.530 mmol) was dissolved in MeOH and thenpassed through NaHCO₃ resin (500 mg; 0.9 mmol). The solution wasconcentrated to yield the free base (230 mg). The free base wasdissolved in 9:1 CH₂Cl₂/pyridine (3 mL) added ethyl3-chloro-3-oxopropanoate (160 mg, 1.060 mmol). The resulting mixture wasstirred at rt for 24 h and then concentrated. The residue was taken upwith EtOH (1 mL) and treated with piperidine (20 uL). The resultingmixture was stirred at 65° C. for 24 h and then concentrated. Theresidue was purified by preparative HPLC (MeOH/H₂O/TFA) to yield thedesired product (100 mg, 33%) as a foam. LCMS Anal. Calc'd forC₂₆H₂₃F₈NO₄ 565.15, found [M+H] 566.1.

Intermediate 1031.5,5-Difluoro-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxylicacid

To a solution of Intermediate 103H (100 mg, 0.177 mmol) in MeOH (2 mL)was added 2 M LiOH (0.4 mL, 0.800 mmol). The resulting mixture wasstirred at 100° C. for 15 min. LC-MS indicated the product to be themajor component along with a trace amount of SM and 14% of thecorresponding methyl ester. 2 M LiOH (100 uL) was then added and thereaction was stirred at 100° C. for an additional 15 min. The reactionwas concentrated, acidified with 1 N HCl, and extracted with EtOAc. Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated to yield the desired product (75 mg, 78%) as a solid. LCMSAnal. Calc'd for C₂₄H₁₉F₈NO₄ 537.12, found [M+H] 537.9.

Example 103

To a solution of Intermediate 1031 (20 mg, 0.037 mmol) in MeCN (1 mL)was added 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (7.60 mg, 0.056 mmol),4-aminobenzonitrile (6.59 mg, 0.056 mmol), and EDC (10.70 mg, 0.056mmol). The resulting mixture was stirred at rt overnight. The reactionmixture was diluted with MeCN and purified by preparative HPLC(MeCN/H₂O/TFA) to yield the desired product (11 mg, 46%) as a solid.LCMS Anal. Calc'd for C₃₁H₂₃F₈N₃O₃ 637.16, found [M+H] 637.9. ¹H NMR(500 MHz, CD₃OD) δ 7.67 (d, J=9.08 Hz, 2H), 7.56-7.63 (m, 4H), 7.22-7.26(m, 2H), 7.15-7.20 (m, 2H), 7.04-7.09 (m, 2H), 4.12 (t, J 6.05 Hz, 2H),2.33-2.44 (m, 2H), 2.30 (s, 3H), 2.02-2.09 (m, 2H).

Example 104.(S)-3-Amino-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one

Intermediate 104A.(S)-2-(1,3-Dioxoisoindolin-2-yl)-N-(1,1,1-trifluoro-4-oxo-4-p-tolyl-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)acetamide

To a solution of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (592 mg, 2.88mmol) in dry DCM (10 mL) was added PPh₃ (2269 mg, 8.65 mmol) fairyrapidly, and then CCl₃CN (500 mg, 3.46 mmol) was added dropwise. Themixture was stirred at rt for 3 h and a solution of Intermediate 2F,isomer 2 (500 mg, 1.15 mmol) in dry DCM (3 mL), followed by pyridine(0.3 mL) were added. The mixture was stirred at rt overnight. Themixture was diluted with DCM (10 mL) and washed with sat'd NaHCO₃ (2×8mL). The organic layer was dried over anhydrous MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatography toyield the desired product (620 mg, 87%). LCMS Anal. Calc'd forC₃₁H₂₆F₆N₂O₅ 620.17, found [M+H] 621.3.

Intermediate 104B.(S)-2-(2-Oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridin-3-yl)isoindoline-1,3-dione

Intermediate 104A (145 mg, 0.234 mmol) was dissolved in MeOH (2.2 mL)and then 1 N NaOH (0.2 mL) was added. The mixture was stirred at 69° C.for 45 min and added another 0.2 mL of 1 N NaOH. The reaction was heatedat 130° C. under microwave conditions for 10 min. The mixture wasneutralized with 1 N HCl and then concentrated. The residue was purifiedby silica gel chromatography (12 g silica gel, eluted with EtOAc inhexanes) to yield the desired product (80 mg, 57%). LCMS Anal. Calc'dfor C₃₁H₂₄F₆N₂O₄ 602.16, found [M+H] 603.3.

Example 104

To a solution of Intermediate 104B (80 mg, 0.133 mmol) in 1 mL of EtOHwas added 1 mL of 2 N MeNH₂ in MeOH. The mixture was stirred at 67° C.for 24 h. The solvent was removed in vacuo and the crude product waspurified by silica gel chromatography (4 g silics gel, eluted with EtOAcin hexanes) to yield the desired product (32.3 mg, 52%) as a light brownsolid. LCMS Anal. Calc'd for C₂₃H₂₂F₆N₂O₂ 472.16, found [M+H] 473.2. ¹HNMR (500 MHz, CD₃OD) δ 7.49 (d, J=8.8 Hz, 2H), 7.31-7.17 (m, 4H),7.04-6.92 (m, 2H), 4.08 (s, 2H), 3.46 (d, J=16.2 Hz, 1H), 3.21 (d,J=16.2 Hz, 1H), 2.44-2.30 (m, 5H), 2.09-1.99 (m, 2H).

Example 105.(S)-2-Methyl-N-(2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridin-3-yl)benzamide

To a solution of 104 (15 mg, 0.032 mmol) in dry DCM (0.5 mL) was added2-methylbenzoyl chloride (5.4 mg, 0.035 mmol) and pyridine (2.8 μL,0.035 mmol). The mixture was stirred at rt for 2 h and thenconcentrated. The residue was purified by preparative HPLC(MeCN/H₂O/TFA) to yield the desired product. LCMS Anal. Calc'd forC₃₁H₂₈F₆N₂O₃ 590.20, found [M+H] 591.3. ¹H NMR (500 MHz, CD₃OD) δ 7.56(d, J=8.80 Hz, 2H), 7.11-7.29 (m, 8H), 6.98 (d, J=9.08 Hz, 2H), 4.06 (t,J=6.05 Hz, 2H), 3.73 (d, J=17.06 Hz, 1H), 3.46 (d, J=16.78 Hz, 1H), 2.33(s, 3H), 2.30-2.42 (m, 2H), 2.22 (s, 3H), 1.98-2.06 (m, 2H).

Example 106.(S)-3-Phenoxy-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one

Intermediate 106A.(S)-2-Phenoxy-N-(1,1,1-trifluoro-4-oxo-4-p-tolyl-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)acetamide

To a mixture of triphenylphosphine (138 mg, 0.318 mmol) in dry DCM (0.8mL) was added 2-phenoxyacetic acid (26 mg, 0.173 mmol), followed bytrichloroacetonitrile (30 mg, 0.208 mmol). The mixture was stirred at rtfor 2.5 h. To the mixture was added a solution of Intermediate 2F,isomer 2 (30 mg, 0.069 mmol) in dry DCM (0.5 mL) followed by pyridine(17 μL, 0.208 mmol). The reaction was stirred at rt overnight. Themixture was concentrated and purified by preparative HPLC (MeOH/H₂O/TFA)to yield the desired product (27 mg, 69%) as a brown oil. LCMS Anal.Calc'd for C₂₉H₂₇F₆NO₄ 567.18, found [M+H] 568.3.

Example 106

To a solution of Intermediate 106A (26 mg, 0.046 mmol) in MeOH (0.5 mL)was added 1 N NaOH (60 μL). The mixture was heated at 130° C. undermicrowave conditions for 10 min. The mixture was neutralized with 1 NHCl and concentrated. The residue was purified by preparative HPLC(MeCN/H₂O/TFA) to yield the desired product (1.5 mg, 6%) as a lightbrown oil. LCMS Anal. Calc'd for C₂₉H₂₅F₆NO₃ 549.17, found [M+H] 550.3.¹H NMR (500 MHz, CD₃OD) δ 7.59 (d, J=8.80 Hz, 2H), 7.33 (d, J=8.25 Hz,2H), 7.13 (d, J=8.25 Hz, 2H), 7.01-7.08 (m, 4H), 6.85-6.90 (m, 1H), 6.38(dd, J=8.67, 0.96 Hz, 2H), 4.10-4.15 (m, 2H), 3.71-3.76 (m, 1H),3.61-3.67 (m, 1H), 2.34-2.45 (m, 2H), 2.30 (s, 3H), 2.02-2.11 (m, 2H).

Example 107.6-(4-Butoxyphenyl)-6-methyl-2-oxo-4-p-tolyl-1,2,5,6-tetrahydropyridine-3-carbonitrile

Intermediate 107A.(Z)—N-(1-(4-Butoxyphenyl)ethylidene)-2-methylpropane-2-sulfinamide

To a stirred solution of 1-(4-butoxyphenyl)ethanone (3 g, 15.60 mmol)and 2-methylpropane-2-sulfinamide (2.84 g, 23.41 mmol) in THF (50 mL)was added tetraethoxytitanium (8.90 g, 39.0 mmol). The reaction washeated to 70° C. for 3 d. Cold water was added and the reaction wasstirred vigorously for 20 min. The mixture was filtered through Celite®and the filtrated was diluted with EtOAc. The organic solution waswashed with H₂O, brine, dried over MgSO₄, filtered and concentrated. Thecrude product was by silica gel chromatography (220 g silica gel, elutedwith EtOAc in hexanes) to yield the desired product (4 g, 87%) as ayellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J=8.80 Hz, 2H), 6.91 (d,J=8.80 Hz, 2H), 4.02 (t, J=6.46 Hz, 2 H), 2.73 (s, 3H), 1.75-1.83 (m,2H), 1.46-1.56 (m, 2H), 1.32 (s, 9H), 0.99 (t, J=7.43 Hz, 3H).

Intermediate 107B. Methyl3-(4-butoxyphenyl)-3-(1,1-dimethylethylsulfinamido)butanoate

To a stirred solution of diisopropylamine (3.86 mL, 27.1 mmol) in THF(40 mL) at −78° C. was added n-butyllithium (22.57 mL, 27.1 mmol)dropwise. The reaction was slowly warmed up to −20° C. and stirred for45 min. The reaction was cooled to −78° C. and methyl acetate (2.006 g,27.1 mmol) was added dropwise. After 30 min, chlorotitaniumtriisopropoxide (8.09 mL, 33.8 mmol) in THF (40 mL) was added dropwise.The reaction was stirred at −78° C. for 1 h. Intermediate 107A (4 g,13.54 mmol) in THF (15 mL) was added dropwise and the reaction wasstirred at −78° C. for 2 h. The reaction was quenched by addition ofsat'd NH₄Cl solution and stirred vigorously while warmed to rt. Themixture was filtered through Celite® and washed with EtOAc. The filtratewas washed with H₂O, brine, dried over MgSO₄, filtered and concentrated.The crude product was purified by silica gel chromatography (220 gsilica gel, eluted with EtOAc in hexanes) to yield the desired product(4.33 g, 87%) as a light yellow oil. LCMS Anal. Calc'd for C₁₉H₃₁NO₄S369.20, found [M+H] 370.2. ¹H NMR (500 MHz, CDCl₃) δ 7.31 (d, J=8.80 Hz,2H), 6.85 (d, J=8.80 Hz, 2H), 3.95 (t, J=6.46 Hz, 2H), 3.62 (s, 3H),2.05 (s, 2H), 1.74-1.80 (m, 2H), 1.74 (s, 3H), 1.44-1.54 (m, 2H), 1.29(s, 9H), 0.98 (t, J=7.43 Hz, 3H).

Intermediate 107C. Methyl 3-amino-3-(4-butoxyphenyl)butanoate

To a stirred solution of Intermediate 107B (1 g, 2.71 mmol) in MeOH (6mL) was added 4 N HCl (3.38 mL, 13.53 mmol). The reaction was stirred atrt for 4 h. The reaction mixture was concentrated in vacuo and dilutedwith EtOAc. The organic layer was washed with saturated NaHCO₃, driedover MgSO₄, filtered and concentrated to yield the desired product (700mg, 97%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.38 (d, J=8.80 Hz,2H), 6.86 (d, J=8.80 Hz, 2H), 3.95 (t, J 6.46 Hz, 2H), 3.59 (s, 3H),1.73-1.80 (m, 2H), 1.53 (s, 2H), 1.45-1.52 (m, 2H), 1.19 (s, 3H), 0.98(t, J 7.29 Hz, 3H).

Intermediate 107D. Methyl3-(4-butoxyphenyl)-3-(2-cyanoacetamido)butanoate

To a stirred solution of 2-cyanoacetic acid (128 mg, 1.507 mmol) inCH₂Cl₂ (5 mL) was added oxalyl chloride (0.754 mL, 1.507 mmol) and 1drop of DMF. The reaction was stirred at rt for 1 h and thenconcentrated. The resulting acid chloride was dissolved in CH₂Cl₂ (1 mL)and was then added to Intermediate 107C (200 mg, 0.754 mmol) andpyridine (0.183 mL, 2.261 mmol) in CH₂Cl₂ (5 mL). The reaction wasstirred at rt for 5 h. The reaction mixture was concentrated and theresidue was diluted with EtOAc. The organic layer was washed withsaturated NH₄Cl, dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by silica gel chromatography (24 g silica gel,eluted with EtOAc in hexanes) to yield the desired product (218 mg, 87%)as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 7.22 (d, J=8.80 Hz, 2H), 6.85(d, J=8.80 Hz, 2H), 3.94 (t, J=6.46 Hz, 2H), 3.65 (s, 3H), 3.30 (s, 2H),3.03 (d, J 15.13 Hz, 1H), 2.85 (d, J=15.13 Hz, 1H), 1.80 (s, 3H),1.71-1.78 (m, 2H), 1.44-1.53 (m, 2H), 0.97 (t, J=7.29 Hz, 3H).

Intermediate 107E.6-(4-Butoxyphenyl)-4-hydroxy-6-methyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile

To a stirred solution of Intermediate 107D (218 mg, 0.656 mmol) in MeOH(5 mL) was added 4.37 M NaOMe (0.750 mL, 3.28 mmol) in methanolsolution. The reaction was heated to 55° C. for 5 h. The reactionmixture was concentrated and the residue was diluted with EtOAc. Theorganic layer was washed with 1 M HCl, dried over MgSO₄, filtered andconcentrated to yield the desired product (200 mg, 102%) as a lightyellow solid. LCMS Anal. Calc'd for C₁₇H₂₀N₂O₃ 300.15, found [M+H]301.1.

Intermediate 107F.6-(4-Butoxyphenyl)-4-chloro-6-methyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile

To a stirred solution of Intermediate 107E (130 mg, 0.433 mmol) inClCH₂CH₂Cl (3 mL) was added POCl₃ (0.056 mL, 0.606 mmol) and Hunig'sbase (0.113 mL, 0.649 mmol). The reaction was stirred at rt for 30 minand then heated to 85° C. for 3 h. The reaction mixture was concentratedand the residue was diluted with EtOAc. The organic layer was washedwith saturated NH₄Cl, dried over MgSO₄, filtered and concentrated. Thecrude product was purified by silica gel chromatography (24 g silicagel, eluted with EtOAc in hexanes) to yield the desired product (102 mg,74%) as a white solid. LCMS Anal. Calc'd for C₁₇H₁₉C₁N₂O₂ 318.11, found[M+H] 319.2. ¹H NMR (500 MHz, CDCl₃) δ 7.23 (d, J=8.80 Hz, 2H), 6.90 (d,J=8.80 Hz, 2H), 3.97 (t, J=6.60 Hz, 2H), 2.05 (s, 2H), 1.74-1.82 (m,2H), 1.69 (s, 3H), 1.46-1.55 (m, 2H), 0.99 (t, J=7.43 Hz, 3H).

Example 107

To a stirred solution of Intermediate 107F (11 mg, 0.035 mmol),p-tolylboronic acid (5.63 mg, 0.041 mmol), and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (2.270mg, 3.45 μmol) in dioxane (1 mL) was added CsF (10.48 mg, 0.069 mmol).The reaction was degassed for 10 min and heated to 80° C. for 2 h. Thereaction mixture was concentrated. The residue was diluted with EtOAc,washed with H₂O, brine, dried over MgSO₄, filtered and concentrated. Thecrude material was purified by preparative HPLC (MeOH/H₂O/TFA) to yieldthe desired product (5.7 mg, 44%) as a brown solid. LCMS Anal. Calc'dfor C₂₄H₂₆N₂O₂ 374.20, found [M+H] 375.2. ¹H NMR (400 MHz, CD₃OD) δ 7.41(d, J=8.14 Hz, 2H), 7.32 (d, J=8.80 Hz, 2H), 7.28 (d, J=8.14 Hz, 2H),6.89 (d, J=8.80 Hz, 2H), 3.96 (t, J=6.38 Hz, 2H), 3.46 (d, J=18.05 Hz,1H), 3.24 (d, J=17.83 Hz, 1H), 2.38 (s, 3H), 1.69-1.78 (m, 2H), 1.65 (s,3H), 1.43-1.55 (m, 2H), 0.97 (t, J=7.48 Hz, 3H).

Example 108.6-(5-Hexyloxazol-2-yl)-6-methyl-2-oxo-4-p-tolyl-1,2,5,6-tetrahydropyridine-3-carbonitrile

Intermediate 108A. Ethyl2-(2-cyanoacetamido)-2-methyl-4-oxo-4-p-tolylbutanoate

To a solution of Intermediate 3C (2.192 g, 21.18 mmol) in DCM (30 mL)under argon was added Intermediate 102C (1.2 g, 4.81 mmol), pyridine(0.779 mL, 9.63 mmol) and DMAP (0.059 g, 0.481 mmol). The reactionmixture was stirred at rt for 1 h. The reaction mixture was loaded ontosilica gel (25 g) and washed with EtOAc (4×50 mL). The filtrate wasconcentrated in vacuo to a dark red oil. The oil was dissolved in EtOAc(100 mL) and washed with water (2×50 mL). The organic phase was driedover MgSO₄ and concentrated in vacuo. The residue was purified by silicagel chromatography (80 g silica gel, eluted with EtOAc in hexanes) toafford the desired product (1.28 g, 84%) as yellow oil. LCMS Anal.Calc'd for C₁₇H₂₀N₂O₄ 316.1, found [M+H] 317.1. ¹H NMR (500 MHz, CDCl₃)δ 7.82 (d, J=8.0 Hz, 2H), 7.39 (s, 1H), 7.24-7.29 (m, 2H), 4.45 (d,J=18.2 Hz, 1H), 4.22-4.31 (m, 2H), 3.47 (d, J=18.2 Hz, 1H), 3.28-3.38(m, 2H), 2.42 (s, 3H), 1.74 (s, 3H), 1.24 (t, J=7.0 Hz, 3H).

Intermediate 108B. Ethyl5-cyano-2-methyl-6-oxo-4-p-tolyl-1,2,3,6-tetrahydropyridine-2-carboxylate

Intermediate 108A (1.2837 g, 4.06 mmol) was dissolved in a mixture ofTHF (15 mL) and water (3.00 mL) in a 25 mL 1 neck pear shaped flask thatwas equipped with a magnetic stirrer. Lithium hydroxide monohydrate(0.204 g, 4.87 mmol) was added and the reaction mixture was stirred atrt for 1 h. The reaction mixture was acidified to pH 4 with AcOH,diluted with EtOAc (50 mL) and the solution was washed with water (20mL). The organic phase was dried over MgSO₄ and concentrated in vacuo togive the desired product (1.40 g, 115%) as yellow oil. LCMS Anal. Calc'dfor C₁₇H₁₈N₂O₃ 298.1, found [M+H] 299.1.

Intermediate 108C.5-Cyano-2-methyl-6-oxo-4-p-tolyl-1,2,3,6-tetrahydropyridine-2-carboxylicacid

Intermediate 108B (1.211 g, 4.06 mmol) was dissolved in acetic acid (95mL) in a 250 mL 1 neck pear shaped flask that was equipped with amagnetic stirrer. HCl (11.67 mL, 142 mmol) was added and the reactionmixture was stirred at 60° C. overnight. The reaction mixture wasconcentrated in vacuo to give the desired product as a pale yellowsolid. LCMS Anal. Calc'd for C₁₅H₁₄N₂O₃ 270.1, found [M+H] 271.0. ¹H NMR(500 MHz, CDCl₃) δ 7.48 (d, J=8.3 Hz, 2H), 7.23 (d, J=7.7 Hz, 2H), 3.39(d, J=18.2 Hz, 1H), 2.83 (d, J=18.2 Hz, 1H), 2.35 (s, 3H), 1.54 (s, 3H).

Intermediate 108D. Ethyl 5-hexyloxazole-4-carboxylate

Ethyl 2-isocyanoacetate (1.0 g, 8.84 mmol) was dissolved in DMF (5 mL)in a 25 mL 1 neck pear shaped flask that was equipped with a magneticstirrer and an Ar inlet. DBU (1.999 mL, 13.26 mmol) and heptanoylchloride (1.770 mL, 11.49 mmol) were added and the reaction mixture wasstirred at 80° C. for 6 h. The reaction mixture was poured into water(50 mL) and extracted with EtOAc (3×30 mL). The phases were separatedand the organic phase was dried over MgSO₄ and concentrated in vacuo toa a dark oil. The desired product was isolated by distillation at 90-95°C. at 0.3 mmHg as a clear oil (0.89 g, 45%). LCMS Anal. Calc'd forC₁₂H₁₉NO₃ 225.1, found [M+H] 226.1. ¹H NMR (500 MHz, CDCl₃) δ 7.76 (s,1H), 4.37 (q, J=7.2 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H), 1.71-1.64 (m, 2H),1.38 (t, J=7.2 Hz, 3H), 1.35-1.26 (m, 6H), 0.86 (t, J=6.3 Hz, 3H).

Intermediate 108E. 1-Aminooctan-2-one, HCl salt

Intermediate 108D (0.8889 g, 3.95 mmol) was stirred in HCl (16.44 mL, 99mmol) in a 100 mL 1 neck pear shaped flask that was equipped with amagnetic stirrer. The reaction mixture was heated to 100° C. and stirredfor 6 h. The reaction mixture was concentrated in vacuo to a tan solidthat was triturated in ether (15 mL). The slurry was filtered and waswashed with ether (3 mL). The filter cake was dried under vacuum to givethe desired product (0.57 g, 80%) as an off-white solid. ¹H NMR (500MHz, MeOD) δ 3.97 (s, 2H), 2.56 (t, J=7.4 Hz, 2H), 1.62 (quin, J=7.4 Hz,2H), 1.26-1.40 (m, 6H), 0.88-0.93 (m, 3H).

Intermediate 108F.5-Cyano-2-methyl-6-oxo-N-(2-oxooctyl)-4-p-tolyl-1,2,3,6-tetrahydropyridine-2-carboxamide

Intermediate 108C (0.1 g, 0.370 mmol) was dissolved in DCM (4 mL) in a10 mL 1 neck pear shaped flask that was equipped with a magnetic stirrerand an Ar inlet. EDC (0.099 g, 0.518 mmol), HOBT (0.068 g, 0.444 mmol),Intermediate 108E (0.080 g, 0.444 mmol) and DIEA (0.194 mL, 1.110 mmol)were added and the reaction mixture was stirred at rt overnight. Thereaction mixture was concentrated in vacuo to an orange oil that waspurified by silica gel chromatography (40 g silica gel, eluted with0-100% EtOAc in hexanes) to give the desired product (0.09 g, 61%) asyellow oil.

Example 108

Intermediate 108F (0.045 g, 0.114 mmol) was dissolved in1,2-dichloroethane (2 mL) in a 10 mL 1 neck pear shaped flask that wasequipped with a magnetic stirrer and an Ar inlet. POCl₃ (0.042 mL, 0.455mmol) and DIEA (0.089 mL, 0.512 mmol) were added and the reactionmixture was stirred at 85° C. overnight. The reaction mixture was cooledin an ice/water bath and was quenched with water (3 mL). The mixture wasextracted with EtOAc (2×5 mL) and the organic phases were combined,dried over MgSO₄ and concentrated in vacuo to a brown oil. The crudeproduct was purified by preparative HPLC (MeOH/H₂O/TFA) to yield thedesired product (3.5 mg, 8%) as a yellow solid. LCMS Anal. Calc'd forC₂₃H₂₇N₃O₂ 377.2, found [M+H] 378.2. ¹H NMR (500 MHz, CDCl₃) δ 7.60 (d,J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 6.81 (br. s., 1H), 3.65 (d,J=17.9 Hz, 1H), 3.09 (d, J=17.9 Hz, 1H), 2.63 (t, J=7.4 Hz, 2H), 2.43(s, 3H), 1.76 (s, 3H), 1.57-1.67 (m, 2H), 1.23-1.42 (m, 6H), 0.89 (t,J=6.7 Hz, 3H).

Example 109.6-(1-Heptyl-1H-pyrazol-3-yl)-6-methyl-2-oxo-4-p-tolyl-1,2,5,6-tetrahydropyridine-3-carbonitrile

Intermediate 109A.5-Cyano-N-methoxy-N,2-dimethyl-6-oxo-4-p-tolyl-1,2,3,6-tetrahydropyridine-2-carboxamide

Intermediate 108C (0.25 g, 0.925 mmol) was dissolved in DCM (15 mL) in a25 mL 1 neck rb flask that was equipped with a magnetic stirrer and anAr inlet. N,O-Dimethylhydroxylamine (0.062 g, 1.017 mmol), EDC (0.195 g,1.017 mmol) and N-methylmorpholine (0.112 mL, 1.017 mmol) were added andthe reaction mixture was stirred at rt overnight. The reaction solventwas removed under vacuum. The residue was dissolved in EtOAc (10 mL) andwashed with water (5 mL). The organic phaase was dried over MgSO₄ andconcentrated in vacuo to a dark solid. The crude product was purified bysilica gel chromatography (40 g silica gel, eluted with 0-100% EtOAc inhexanes) to give the desired product (0089 g, 31%) as a white solid.LCMS Anal. Calc'd for C₁₇H₁₉N₃O₃ 313.3, found [M+H] 314.1. ¹H NMR (500MHz, CDCl₃) δ 7.67 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 3.81 (s,3H), 3.69-3.75 (m, 1H), 3.22 (s, 3H), 2.72 (d, J=17.6 Hz, 1H), 2.42 (s,3H), 1.63 (s, 3H).

Intermediate 109B.6-Methyl-2-oxo-6-propioloyl-4-p-tolyl-1,2,5,6-tetrahydropyridine-3-carbonitrile

Intermediate 109A (0.0887 g, 0.283 mmol) was dissolved intetrahydrofuran (1 mL) in a 25 mL 1 neck pear shaped flask that wasequipped with a magnetic stirrer and an Ar inlet. Ethynylmagnesiumbromide (5.66 mL, 2.83 mmol) was added dropwise and the reaction mixturewas stirred at 35° C. for 4 h. The reaction mixture was cooled to rt,quenched with sat'd. aq NH₄Cl (5 mL) and extracted with EtOAc (2×10 mL).The organic phases were combined and concentrated in vacuo. The residuewas purified by silica gel chromatography (24 g silica gel, eluted with0-100% EtOAc in hexanes) to give the desired product (0.06 g, 78%) as anorange solid. LCMS Anal. Calc'd for C₁₇H₁₄N₂O₂ 278.1, found [M+H] 279.0.

Example 109

Intermediate 109B (0.0613 g, 0.220 mmol) was dissolved in ethanol (3 mL)in a 25 mL 1 neck pear shaped flask that was equipped with a magneticstirrer. Heptylhydrazine, HCl (0.073 g, 0.441 mmol) and TEA (0.061 mL,0.441 mmol) were added and the reaction mixture was stirred at rtovernight. The reaction mixture was concentrated and purified bypreparative HPLC (MeOH/H₂O/TFA) to yield the desired product (3.2 mg,4%) as a white solid. LCMS Anal. Calc'd for C₂₄H₃₀N₄O 390.2, found [M+H]391.2. ¹H NMR (500 MHz, CDCl₃) δ 7.55 (d, J=8.3 Hz, 2H), 7.25-7.30 (m,2H), 6.35 (s, 1H), 6.15 (d, J=1.7 Hz, 1H), 3.98-4.08 (m, 2H), 3.57 (d,J=17.9 Hz, 1H), 3.01 (d, J=17.9 Hz, 1H), 2.41 (s, 3H), 1.81 (quin, J=7.3Hz, 2H), 1.70-1.77 (m, 2H), 1.68 (s, 3H), 1.16-1.34 (m, 6H), 0.87 (t,J=7.0 Hz, 3H).

Examples 110-273 expressed by Formula (II), unless noted in the table,may be made by one skilled in the art by appropriate application of theprocedures described for Examples 1-16 and Examples 102-. R¹¹ to R¹⁵ arehydrogen, unless noted in the table.

(II)

Example R¹ R² R³ = R⁴ R⁶ R¹¹-R¹⁵ [M + H] ¹HNMR (400 MHz, CDCl₃) 110S-isomer

CF₃ H

R¹³ = CH₃ 608.1 8.13 (d, J = 2.5 Hz, 1H), 7.93 (dd, J = 9.1, 2.8 Hz,1H), 7.46 (d, J = 9.1 Hz, 2H), 7.22 (s, 1H), 7.20-7.15 (m, 2H),7.13-7.08 (m, 2H), 6.94 (d, J = 9.1 Hz, 2H), 6.67 (d, J = 9.1 Hz, 1H),4.02 (t, J = 5.9 Hz, 2H), 3.90 (br. s., 3H), 3.56-3.38 (m, 2H),2.39-2.25 (m, 5H), 2.10-2.01 (m, 2H). 111 S-isomer

CF₃ H

R¹³ = CH₃ 645.2 7.88 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.54(d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.7 Hz, 2H),7.00 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.9 Hz, 2H), 3.75-3.46 (m, 2H),2.43- 2.32 (m, 2H), 2.29 (s, 3H), 2.11-1.97 (m, 2H). 112 Rac

CF₃ H

R¹³ = CH₃ 480.0 113 S-isomer

CF₃ H

R¹³ = CH₃ 526.1 9.07 (d, J = 1.1 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H),7.16-7.09 (m, J = 8.0 Hz, 2H), 7.09-7.03 (m, 2H), 6.93-6.86 (d, J = 7.7Hz, 2H), 4.12 (t, J = 6.1 Hz, 2H), 4.00 (s, 1H), 3.92 (d, J = 17.6 Hz,1H), 3.77 (d, J = 17.6 Hz, 1H), 2.46-2.34 (m, 2H), 2.30 (s, 3H),2.12-2.02 (m, 2H). 114 S-isomer

CF₃ H

R¹³ = CH₃ 524.1 115 S-isomer

CF₃ H

R¹³ = CH₃ 577.2 116 Rac

CF₃ H

R¹³ = CH₃ 554.2 7.42 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.10(br. s., 1H), 6.95 (dd, J = 15.0, 8.4 Hz, 4H), 3.97 (t, J = 6.3 Hz, 2H),3.59 (d, J = 5.5 Hz, 2H), 2.36 (s, 3H), 2.16-2.04 (m, 2H), 1.86- 1.77(m, 2H), 1.69-1.59 (m, 2H), 1.59-1.50 (m, 2H), 0.93-0.79 (m, 3H) 117 Rac

CF₃ H

R¹³ = CH₃ 540.1 7.43 (d, J = 8.5 Hz, 2H), 7.17 (d J = 7.7 Hz, 2H),7.03-6.91 (m, 5H), 3.99 (t, J = 5.9 Hz, 2H), 3.65-3.53 (m, 2H), 2.37 (s,3H), 2.23- 2.11 (m, 2H), 1.92-1.82 (m, 2H), 1.82-1.72 (m, 2H) 118 Rac

CF₃ H

R¹³ = CH₃ 576.1 7.44 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.96(dd, J = 11.4, 8.7 Hz, 4H), 6.80 (br. s., 1H), 4.07- 4.01 (m, 2H), 3.59(d, J = 7.4 Hz, 2H), 2.37 (s, 3H), 2.33-2.19 (m, 2H), 2.10 (dd, J = 9.5,5.6 Hz, 2H) 119 S-isomer

CF₃ H

R¹³ = CH₃ 541.2 7.44 (d, J = 8.3 Hz, 2H), 7.21-7.16 (m, 2H), 7.14- 7.09(m, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 5.9 Hz, 3H), 3.58-3.27(m, 2H), 2.48-2.27 (m, 5H), 2.09 (dd, J = 9.5, 5.9 Hz, 2H), 0.97- 0.80(m, 2H), 0.75-0.61 (m, 2H), 0.38 (d, J = 3.6 Hz, 2H) 120 S-isomer

CF₃ H

R¹³ = CH₃ 555.2 7.43 (d, J = 8.5 Hz, 2H), 7.20-7.03 (m, 5H), 6.97- 6.88(m, 2H), 4.36-4.22 (m, 1H), 4.08-3.98 (m, 2H), 3.53-3.27 (m, 2H), 2.44-2.16 (m, 8H), 2.12-2.02 (m, 2H), 1.78-1.51 (m, 4H) 121 S-isomer

CF₃ H

R¹³ = CH₃ 583.3 7.49-7.37 (m, 2H), 7.22- 7.07 (m, 4H), 6.97-6.84 (m,3H), 6.74 (d, J = 8.0 Hz, 1H), 4.10-3.95 (m, 3H), 3.77-3.62 (m, 1H),3.52- 3.26 (m, 2H), 2.42-2.25 (m, 6H), 2.15-1.96 (m, 3H), 1.86-1.64 (m,2H), 1.64- 1.44 (m, 4H), 1.35-1.16 (m, 3H), 1.14-0.93 (m, 4H) 122S-isomer

CF₃ H

R¹³ = CH₃ 593.3 7.55 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.20(d, J = 8.0 Hz, 2H), 7.14-7.09 (d, J = 8.8 Hz, 2H), 7.02-6.97 (d, J =8.8 Hz, 2H), 6.68-6.62 (m, 2H), 4.08 (t, J = 6.1 Hz, 2H), 3.67 (d, J =17.1 Hz, 1H), 3.51 (d, J = 17.1 Hz, 1H), 2.45-2.35 (m, 2H), 2.34 (s,3H), 2.09- 2.00 (m, 2H). 123 S-isomer

CF₃ H

R¹³ = CH₃ 515.2 7.57-7.50 (m, J = 8.8 Hz, 2H), 7.27-7.23 (m, J = 8.3 Hz,2H), 7.23-7.19 (m, J = 8.3 Hz, 2H), 7.02-6.97 (m, J = 9.1 Hz, 2H), 4.08(t, J = 6.1 Hz, 2H), 3.60 (d, J = 17.1 Hz, 1H), 3.46 (d, J = 17.1 Hz,1H), 2.57 (s, 3H), 2.45-2.37 (m, 2H), 2.36 (s, 3H), 2.11-1.99 (m, 2H).124 Rac

CF₃ F

R¹³ = CH₃ 643.3 7.90 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.25-7.17 (m,6H), 6.98 (d, J = 8.8 Hz, 2H), 6.95 (br. s., 1H), 6.78 (d, J = 9.1 Hz,2H), 4.05 (t, J = 5.9 Hz, 2H), 3.81-3.71 (m, 3H), 2.44-2.27 (m, 5H),2.13- 2.03 (m, 2H) 125 Rac

CF₃ H

R¹³ = CH₃ 512.1 7.45 (d, J = 8.5 Hz, 3H), 7.13 (d, J = 7.7 Hz, 2H), 6.93(d, J = 7.7 Hz, 4H), 4.18 (t, J = 6.5 Hz, 2H), 3.68- 3.52 (m, 2H),2.67-2.56 (m, 2H) 126 Rac

CF₃ H

R¹³ = CH₃ 466.2 127 Rac

CF₃ H

R¹³ = CH₃ 480.1 7.50-7.40 (m, 4H), 7.16 (d, J = 7.7 Hz, 2H), 7.09 (br.s., 1H), 6.98 (d, J = 7.7 Hz, 2H), 6.17 (br. s., 1H), 2.36 (s, 5H), 2.21(d, J = 3.6 Hz, 2H), 1.82-1.74 (m, 2H), 1.70-1.62 (m, 2H) 128 S-isomer

CF₃ H

R¹³ = CH₃ 591.3 129 S-isomer

CF₃ H

R¹³ = CH₃ 591.3 130 S-isomer

CF₃ H

R¹³ = CH₃ 568.2 8.47 (d, J = 1.9 Hz, 1H), 7.61-7.54 (ab quartet, J = 8.8Hz, 2H), 7.24-7.20 (ab quartet, J = 8.3 Hz, 2H), 7.19-7.15 (ab quartet,J = 8.3 Hz, 2H), 7.04-6.98 (m, 2H), 6.93-6.87 (m, 1H), 4.09 (t, J = 6.1Hz, 2H), 3.75 (d, J = 17.1 Hz, 1H), 3.51 (d, J = 16.8 Hz, 1H), 2.46-2.34(m, 2H), 2.32 (s, 3H), 2.12- 2.01 (m, 3H). 131 S-isomer

CF₃ H

R¹³ = CH₃ 581.3 132 S-isomer

CF₃ H

R¹³ = CH₃ 570.2 133 Rac

CF₃ F

R¹³ = CH₃ 643.1 8.07 (br. s., 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.24-7.15(m, 6H), 6.96 (d, J = 9.1 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 4.09-3.97(m, 2H), 3.75 (s, 3H), 2.39-2.25 (m, 5H), 2.12-2.02 (m, 2H) 134 Rac

CF₃ F

R¹³ = CH₃ 680.9 135 Rac

CF₃ F

R¹³ = CH₃ 626.9 136 S-isomer

CF₃ H

R¹³ = CH₃ 594.1 137 S-isomer

CF₃ H

R¹³ = CH₃ 661.1 138 Rac

CF₃ F CN R¹³ = CH₃ 422.8 140 Rac

CF₃ F

R¹³ = CH₃ 643.9 141 Rac

CF₃ F

R¹³ = CH₃ 604.9 142 S-isomer

CF₃ H

R¹¹ = F R¹³ = OCH₃ 560.1 9.17 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H),7.07-7.00 (m, 2H), 6.95 (t, J = 8.5 Hz, 1H), 6.69 (dd, J = 8.8, 2.5 Hz,1H), 6.63 (dd, J = 12.7, 2.5 Hz, 1H), 4.09 (t, J = 6.1 Hz, 2H),3.90-3.81 (m, 1H), 3.76 (s, 3H), 3.74-3.66 (m, 1H), 2.47-2.30 (m, 2H),2.12- 1.94 (m, 2H). 143 S-isomer

CF₃ H

R¹³ = OCH₃ 542.1 9.05 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.04 (d, J =9.1 Hz, 2H), 6.97-6.88 (m, 1H), 6.86-6.76 (m, 1H), 4.09 (t, J = 6.1 Hz,2H), 3.92-3.70 (m, 2H), 3.75 (S, 3H), 2.45- 2.29 (m, 2H), 2.10-1.94 (m,2H). 144 S-isomer

CF₃ H CN R¹³ = OCHF₂ 535.1 7.65 (br. s., 2H), 7.53 (d, J = 9.1 Hz, 2H),7.32-7.24 (m, 2H), 7.05-6.98 (m, 2H), 6.96 (t, J = 75 Hz, 1H), 4.14-3.97 (m, 2H), 3.73 (d, J = 3.3 Hz, 2H), 2.42-2.27 (m, 2H), 2.09-1.96 (m,2H). 145 S-isomer

CF₃ H CN R¹³ = OCH₂CH₃ 513.1 7.64 (d, J = 9.1 Hz, 2H), 7.52 (d, J = 9.1Hz, 2H), 7.03 (d, J = 9.1 Hz, 4H), 4.12 (d, J = 6.9 Hz, 2H), 4.08-4.03(m, 2H), 3.82-3.58 (m, 2H), 2.45-2.26 (m, 2H), 2.08- 1.95 (m, 2H), 1.41(t, J = 6.9 Hz, 3H). 146 S-isomer

CF₃ H CN

519.1 8.15 (d, J = 1.7 Hz, 1H), 8.01- 7.96 (m, 2H), 7.93 (d, J = 8.0 Hz,1H), 7.67-7.54 (m, 5H), 7.06-7.00 (m, 2H), 4.08 (s, 2H), 3.93-3.77 (m,2H), 2.48-2.25 (m, 2H), 2.13-1.92 (m, 2H). 147 S-isomer

CF₃ H CN R¹³ = CH₃ 469.1 7.55 (d, J = 8.8 Hz, 2H), 7.52- 7.49 (m, 2H),7.33 (d, J = 8.0 Hz, 2H), 7.04-6.99 (m, 2H), 4.24 (t, J = 6.1 Hz, 2H),3.77-3.66 (m, 2H), 2.75- 2.63 (m, 2H), 2.41 (s, 3H). 148 S-isomer

CF₃ H

R¹¹ = CH₃ R¹³ = CH₃ 621.2 7.49-7.41 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H),7.03-6.65 (m, 7H), 4.07-3.99 (m, 2H), 3.71 (s, 3H), 3.51-3.42 (m, 1H),3.28-3.14 (m, 1H), 2.38-2.21 (m, 8H), 2.11- 1.99 (m, 2H). 149 S-isomer

CF₃ H

R¹³ = OCHF₂ 578.1 □□9.09 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.08-7.03(m, 6H), 6.97-6.68 (m, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.92 (d, J = 17.9Hz, 1H), 3.77 (d, J = 17.9 Hz, 1H), 2.43-2.31 (m, 2H), 2.10-1.98 (m,2H). 150 S-isomer

CF₃ F

R¹³ = CH₃ 582.2 7.54 (d, J = 8.8 Hz, 2H), 7.23-7.11 (m, 4H), 7.03- 6.94(m, 2H), 6.71 (s, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.98 (s, 1H), 3.71 (d,J = 17.1 Hz, 1H), 3.47 (d, J = 16.8 Hz, 1H), 2.45-2.31 (m, 2H), 2.29 (d,J = 6.3 Hz, 6H), 2.12-1.96 (m, 2H). 151 S-isomer

CF₃ H

R¹³ = CH₃ 568.2 152 S-isomer

CF₃ H

R¹³ = CH₃ 568.2 153 S-isomer

CF₃ H

R¹³ = CH₃ 579.2 154 S-isomer

CF₃ H

R¹³ = CH₃ 583.1 7.58-7.49 (ab quartet, J = 8.8 Hz, 2H), 7.20 (d, J = 8.3Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.03-6.92 (m, 2H), 4.06 (t, J = 6.1Hz, 2H), 3.72 (d, J = 17.3 Hz, 1H), 3.49 (d, J = 17.1 Hz, 1H), 2.55 (s,3H), 2.43-2.33 (m, 2H), 2.30 (s, 3H), 2.09-1.97 (m, 2H). 155 Rac

CH₃ H

R¹³ = CH₃ 478.4 156 S-isomer

CF₃ H

R¹¹ = CH₃ R¹³ = CH₃ 540.1 157 S-isomer

CF₃ H

R¹³ = CH₃ 582.2 158 S-isomer

CF₃ H

R¹³ = CH₃ 613.2 159 Rac

CF₃ F

R¹³ = CH₃ 562.2 160 Rac

CF₃ F CN R¹³ = CH₃ 519.2 161 Rac

CH₃ H

R¹³ = CH₃ 464.3 162 Rac

CF₃ F

R¹³ = CH₃ 628.9 163 Rac

CF₃ F

R¹³ = CH₃ 656.9 8.05 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.25-7.16 (m,6H), 7.02-6.94 (m, 2H), 6.82- 6.73 (m, 2H), 6.60 (br. s., 1H), 4.01 (td,J = 6.1, 1.4 Hz, 2H), 3.75 (s, 3H), 2.35 (s, 3H), 2.24-2.10 (m, 2H),1.93-1.85 (m, 2H), 1.83- 1.74 (m, 2H), 1.67 (br. s., 3H) 164 Rac

CF₃ F

R¹³ = CH₃ 671.0 165 S-isomer

CF₃ H

R¹³ = CH₃ 561.2 7.59 (d, J = 8.8 Hz, 2H), 7.42-7.36 (m, 2H), 7.35-0 7.28(m, 4H), 7.20-7.16 (m, 3H), 7.06-6.99 (m, 4H), 6.98-6.93 (m, 2H), 3.66(d, J = 17.3 Hz, 1H), 3.52 (d, J = 17.3 Hz, 1H), 2.30 (s, 3H). 166 Rac

CH₃ H

R¹³ = CH₃ 492.2 167 S-isomer

CF₃ H

R¹³ = OHCF₂ 620.2 8.38 (d, J = 1.7 Hz, 1H), 7.61 (s, 1H), 7.51 (d, J =8.8 Hz, 2H), 7.34-7.24 (m, 2H), 7.13-7.04 (ab quartet, J = 8.8 Hz, 2H),6.99-6.92 (m, 2H), 6.86 (s, 1H), 4.26 (br. s., 1H), 4.05 (t, J = 5.9 Hz,2H), 3.69 (d, J = 17.1 Hz, 1H), 3.42 (d, J = 17.1 Hz, 1H), 2.41-2.27 (m,2H), 2.10-1.97 (m, 2H). 168 S-isomer

CF₃ H

R¹³ = CH₃ 611.2 169 S-isomer

CF₃ H

R¹³ = CH₃ 611.2 170 S-isomer

CF₃ H

R¹³ = CH₃ 629.2 171 S-isomer

CF₃ H

R¹³ = CH₃ 629.3 172 S-isomer

CF₃ H

R¹³ = OCH₃ 584.2 8.37 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H),7.28-7.17 (m, 2H), 6.99- 6.91 (m, 2H), 6.89-6.82 (m, 3H), 4.05 (t, J =6.1 Hz, 2H), 3.78 (s, 3H), 3.68 (d, J = 16.8 Hz, 1H), 3.42 (d, J = 17.1Hz, 1H), 2.45-2.23 (m, 2H), 2.10-1.98 (m, 2H). 173 Rac

CH₃ H

R¹³ = CH₃ 618.4 7.34 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 9.1 Hz, 2H), 7.15(d, J = 8.0 Hz, 2H), 6.79 (d, J = 9.1 Hz, 2H), 3.76 (s, 3H), 3.43-3.37(d, J = 17.5 Hz, 1H), 3.22 (t, J = 7.1 Hz, 2H), 2.86-2.80 (d, J = 17.2Hz, 1H), 2.32 (s, 3H), 1.53 (s, 3H), 1.31-1.21 (m, 28H), 0.88 (t, J =7.1 Hz, 3H) 174 Rac

CH₃ H

R¹³ = CH₃ 506.4 175 Rac

CH₃ H

R¹³ = CH₃ 512.4 176 S-isomer

CF₃ H

R¹³ = OCH₃ 598.2 7.54 (d, J = 8.8 Hz, 2H), 7.32-7.23 (m, 2H), 6.97 (d, J= 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.73 (s, 1H), 4.06 (t, J = 6.1Hz, 2H), 3.76 (s, 3H), 3.71 (d, J = 17.1 Hz, 1H), 3.49 (d, J = 17.1 Hz,1H), 2.45-2.32 (m, 2H), 2.31-2.26 (m, 3H), 2.08- 1.97 (m, 2H). 177 Rac

CH₃ H CN R¹³ = CH₃ 382.3 178 Rac

CH₃ H

R¹³ = CH₃ 526.4 179 S-isomer

CF₃ H

R¹³ = CH₃ 648.2 7.54 (d, J = 8.8 Hz, 2H), 7.23-7.11 (m, 4H), 7.03- 6.93(m, 3H), 4.06 (t, J = 6.1 Hz, 2H), 3.72 (d, J = 16.9 Hz, 1H), 3.48 (d, J= 17.2 Hz, 1H), 2.44-2.32 (m, 2H), 2.30 (s, 3H), 2.08-1.97 (m, 2H). 180S-isomer

CF₃ H

R¹³ = CH₃ 674.3 181 Rac

CF₃ F

R¹³ = CH₃ 547.0 182 Rac

CF₃ H

R¹³ = CH₃ 510.3 183 Rac S-isomer

CF₃ H

R¹³ = CH₃ 554.3 7.57-7.48 (m, 2H), 7.13- 7.05 (m, 2H), 7.02-6.94 (m,2H), 6.88-6.77 (m, 2H), 4.07-3.99 (m, 2H), 2.29 (s, 3H), 2.19-2.07 (m,2H), 1.89-1.78 (m, 2H), 1.69- 1.55 (m, 4H) 184 S-isomer

CF₃ H CN R¹³ = CH₃ 511.1 7.46 (dd, J = 12.1, 8.5 Hz, 4H), 7.31 (d, J =8.3 Hz, 2H), 6.95 (d, J = 9.1 Hz, 2H), 4.32-4.22 (m, 1H), 4.00 (s, 2H),3.67-3.55 (m, 1H), 2.41 (s, 3H), 2.23-1.99 (m, 2H), 1.88-1.76 (m, 2H),1.70-1.50 (m, 5H) 185 S-isomer

CF₃ H

R¹³ = CH₃ 678.3 186 S-isomer

CF₃ H

R¹³ = CH₃ 540.3 187 S-isomer

CF₃ H

R¹³ = CH₃ 598.3 7.57-7.50 (m, J = 8.8 Hz, 2H), 7.21-7.12 (m, 4H),7.01-6.94 (m, 2H), 6.48 (s, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.95 (s, 3H),3.71 (d, J = 17.1 Hz, 1H), 3.47 (d, J = 17.1 Hz, 1H), 2.44-2.32 (m, 2H),2.30 (s, 3H), 2.07-1.98 (m, 2H). 188 Rac

CH₃ H

R¹³ = CH₃ 450.1 189 Rac

CH₃ H

R¹³ = CH₃ 484.1 190 S-isomer

CF₃ H

R¹³ = CH₃ 662.3 191 Rac

CH₃ H

R¹³ = CH₃ 520.2 192 S-isomer

CF₃ H

R¹³ = CH₃ 526.3 193 S-isomer

CF₃ H

R¹³ = OCH₃ 542.1 ¹H NMR (500 MHz, CDCl₃: MeOD (1:1)) δ 7.65 (s, 1H),7.54 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.4 Hz,2H), 6.79 (d, J = 8.4 Hz, 2H), 4.07 (t, J = 6.0 Hz, 2H), 3.77 (s, 3H),3.69 (d, J = 17.7 Hz, 1H), 3.60 (d, J = 17.7 Hz, 1H), 2.41-2.28 (m, 2H),2.06 (dq, J = 12.1, 6.3 Hz, 2H). 194 Rac

CF₃ H

R¹³ = CH₃ 432.3 7.21 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.25(s, 1H), 3.39 (d, J = 18.5 Hz, 1H), 3.34 (d, J = 18.9 Hz, 1H), 2.39 (s,3H), 2.23 (t, J = 7.2 Hz, 2H), 1.55- 1.47 (m, 2H), 1.40-1.23 (m, 6H),0.87 (t, J = 6.9 Hz, 3H). 195 Rac

CF₃ H

R¹³ = CH₃ 460.4 7.21 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.32(s, 1H), 3.37 (AB quartet, J = 18.7 Hz, 2H), 2.39 (s, 3H), 2.23 (t, J =7.0 Hz, 2H), 1.51 (quin, J = 7.2 Hz, 2H), 1.39- 1.20 (m, 10H), 0.91-0.84(m, 3H). 196 R-isomer

CF₃ H

R¹³ = CH₃ 460.4 7.17 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.74(s, 1H), 3.43-3.32 (m, 2H), 2.37 (s, 3H), 2.23 (t, J = 7.0 Hz, 2H),1.55-1.47 (m, 2H), 1.37-1.22 (m, 10H). 197 S-isomer

CF₃ H

R¹³ = CH₃ 388.3 7.20 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.34(s, 1H), 3.38, 3.32 (ABq, J = 18.9 Hz, 2H), 2.39 (s, 3H), 1.28 (tt, J =8.3, 5.0 Hz, 1H), 0.89-0.83 (m, 2H), 0.76-0.71 (m, 2H). 198 S-isomer

CF₃ H

R¹³ = CH₃ 452.3 7.30-7.23 (m, 2H), 7.22- 7.13 (m, 5H), 6.99 (d, J = 8.1Hz, 2H), 6.57 (s, 1H), 3.33 (d, J = 18.9 Hz, 1H), 3.26 (d, J = 18.9 Hz,1H), 2.85-2.80 (m, 2H), 2.57- 2.53 (m, 2H), 2.38 (s, 3H) 199 S-isomer

CF₃ H

R¹³ = CH₃ 418.3 7.19 (d, J = 7.9 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.68(s, 1H), 3.38, 3.35 (ABq, J = 18.9 Hz, 2H), 2.37 (s, 3H), 2.24 (t, J =7.4 Hz, 2H), 1.63 (dquin, J = 13.4, 6.7 Hz, 1H), 1.41 (q, J = 7.3 Hz,2H), 0.88 (d, J = 6.6 Hz, 6H) 200 Rac

CF₃ H

R¹³ = CH₃ 663.2 9.63 (s, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.50 (d, J =8.9 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.13(d, J = 8.5 Hz, 2H), 6.87 (s, 1H), 4.13 (t, J = 7.2 Hz, 2H), 3.48 (d, J= 18.4 Hz, 1H), 3.25 (d, J = 18.4 Hz, 1H), 2.42-2.31 (m, 3H), 2.08-2.03(m, 2H), 1.96-1.85 (m, 2H), 1.62- 1.53 (m, 2H), 1.41-1.31 (m, 2H) 201Rac

CF₃ H

R¹³ = CH₃ 645.3 10.16 (s, 1H), 9.00 (s, 1H), 7.99 (s, 1H), 7.70 (s, 1H),7.51 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.3 Hz,2H), 7.12 (t, J = 74.3 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 4.11 (t, J =6.9 Hz, 2H), 3.41-3.37 (d, J = 17.4 Hz, 1H), 3.35-3.31 (d, J = 17.4 Hz,1H), 2.28 (s, 3H), 2.23- 2.17 (m, 2H), 1.85-1.75 (m, 2H), 1.52-1.44 (m,2H), 1.31-1.22 (m, 2H). 202 S-isomer

CF₃ H

R¹³ = CH₂OCH₃ 556.3 ¹HNMR (500 MHz, DMSO- d₆) δ 9.57 (s, 1H), 7.64 (d, J= 8.8 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.99(d, J = 7.9 Hz, 2H), 4.36 (s, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.75 (d, J= 17.5 Hz, 1H), 3.69 (d, J = 17.5 Hz, 1H), 3.27 (s, 3H), 2.48-2.37 (m,2H), 2.01- 1.89 (m, 2H) 203 S-isomer

CF₃ H

R¹² = F R¹³ = OCH₂CH₃ 574.3 204 S-isomer

CF₃ H

R¹³ = CH₃ 512.1 ¹H NMR (500 MHz, MeOD:CDCl₃ (1:1)) δ 7.61 (s, 2H), 7.55(d, J = 8.6 Hz, 2H), 6.97 (dd, J = 10.4, 8.3 Hz, 4H), 6.84 (d, J = 8.1Hz, 2H), 4.24 (t, J = 6.4 Hz, 2H), 3.71 (d, J = 17.2 Hz, 1H), 3.50 (d, J= 17.2 Hz, 1H), 3.08-3.03 (m, 4H), 2.67 (qt, J = 10.8, 6.3 Hz, 2H), 1.78(dq, J = 11.3, 5.5 Hz, 4H), 1.69 (q, J = 5.9 Hz, 2H). 205 S-isomer

CF₃ H

R¹³ = OCHF₂ 578.1 ¹H NMR (500 MHz, CDCl₃: MeOD (1:1)) δ 7.61 (s, 2H),7.54 (d, J = 8.6 Hz, 2H), 7.05- 6.96 (m, 5H), 6.66 (t, J = 73.4 Hz, 1H),4.07 (t, J = 6.0 Hz, 2H), 3.70 (d, J = 17.9 Hz, 1H), 3.57 (d, J = 17.8Hz, 1H), 2.41-2.28 (m, 2H), 2.11-2.02 (m, 2H). 206 S-isomer

CF₃ H

R¹³ = CH₃ 498.1 ¹H NMR (500 MHz, MeOD- CDCl₃ (1:1)) δ 7.60-7.57 (m, 2H),7.07 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H), 4.48 (q, J = 8.2 Hz,1H), 3.70 (d, J = 17.8 Hz, 1H), 3.58 (d, J = 17.8 Hz, 1H), 2.30 (s, 1H).207 S-isomer

CF₃ H

562.1 ¹H NMR (500 MHz, CDCl₃: MeOD (1:1)) δ 7.81-7.73 (m, 2H), 7.72 (d,J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.60-7.55 (m, 3H), 7.53-7.46 (m, 2H),7.01 (d, J = 8.8 Hz, 2H), 6.98 (dd, J = 8.5, 1.8 Hz, 1H), 4.08 (t, J =6.0 Hz, 2H), 3.83 (d, J = 17.8 Hz, 1H), 3.70 (d, J = 17.8 Hz, 1H),2.41-2.28 (m, 2H), 2.11-2.01 (m, 2H). 208 S-isomer

CF₃ H

R¹³ = OCH₂CH₃ 556.1 ¹H NMR (500 MHz, CDCl₃: MeOD (1:1)) δ 7.62 (s, 1H),7.54 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.7 Hz,2H), 6.77 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 6.0 Hz, 2H), 4.00 (q, J =7.0 Hz, 2H), 3.68 (d, J = 17.8 Hz, 1H), 3.59 (d, J = 17.7 Hz, 1H),2.40-2.28 (m, 2H), 2.10-2.01 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H). 209S-isomer

CF₃ H

570.2 ¹H NMR (500 MHz, DMSO- d₆) δ 9.51 (s, 1H), 7.61 (d, J = 8.4 Hz,2H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.4 Hz, 1H), 6.57 (d, J =2.2 Hz, 1H), 6.41 (dd, J = 8.5, 2.2 Hz, 1H), 4.25-4.14 (m, 4H), 4.06 (t,J = 6.2 Hz, 2H), 3.68 (d, J = 18.2 Hz, 1H), 3.63 (d, J = 18.5 Hz, 1H),2.42 (ddd, J = 16.4, 8.0, 5.1 Hz, 2H), 1.93 (dq, J = 12.3, 6.4 Hz, 2H).210 S-isomer

CF₃ H

566.1 ¹H NMR (500 MHz, DMSO- d₆) δ 9.42 (s, 1H), 7.60 (d, J = 8.5 Hz,2H), 7.01 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H),6.56 (d, J = 7.7 Hz, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.67 (d, J = 17.8Hz, 1H), 3.60 (d, J = 17.9 Hz, 1H), 2.61 (s, 2H), 2.56 (s, 2H), 2.42(ddd, J = 11.4, 8.3, 5.2 Hz, 2H), 1.98- 1.88 (m, 2H), 1.65 (p, J = 2.8Hz, 4H). 211 S-isomer

CF₃ H

556.2 ¹H NMR (500 MHz, DMSO- d₆) δ 9.37 (s, 1H), 7.60 (d, J = 8.5 Hz,2H), 7.01 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.57 (s, 1H),6.48 (d, J = 8.1 Hz, 1H), 5.97 (d, J = 3.1 Hz, 2H), 4.06 (t, J = 6.1 Hz,2H), 3.65 (d, J = 17.6 Hz, 1H), 3.58 (d, J = 17.7 Hz, 1H), 2.46-2.35 (m,2H), 1.93 (dd, J = 9.9, 5.4 Hz, 2H). 212 S-isomer

CF₃ H

582.3 ¹H NMR (500 MHz, DMSO- d₆) δ 9.30 (s, 1H), 7.56 (d, J = 8.4 Hz,2H), 6.99 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.2 Hz, 1H), 6.62 (d, J =8.4 Hz, 1H), 4.12-4.01 (m, 2H), 3.70 (s, 3H), 3.67 (m, 1H), 3.60 (d, J =17.4 Hz, 1H), 2.67-2.55 (m, 2H), 2.46- 2.35 (m, 2H), 2.31-2.07 (m, 2H),1.97-1.91 (m, 2H), 1.81-1.69 (m, 2H). 213 S-isomer

CHF₂ H

R¹³ = CH₃ 508.3 ¹H NMR (500 MHz, DMSO- d₆) δ 9.10 (s, 1H), 7.52 (d, J =8.5 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.88(d, J = 7.9 Hz, 2H), 6.33 (t, J = 55.0 Hz, 1H), 4.07 (t, J = 6.2 Hz,2H), 3.57 (d, J = 17.9 Hz, 1H), 3.41 (d, J = 18.2 Hz, 1H), 2.44 (ddd, J= 11.4, 8.1, 5.2 Hz, 2H), 1.99-1.91 (m, 2H). 214 R-isomer

H H

R¹³ = CH₃ 539.4 ¹H NMR (500 MHz, DMSO- d₆) δ 9.97 (s, 1H), 8.06 (s, 1H),7.42 (d, J = 8.6 Hz, 2H), 7.36 (dd, J = 10.3, 8.2 Hz, 4H), 7.13 (d, J =7.9 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H),4.82-4.73 (m, 1H), 4.05 (t, J = 6.2 Hz, 2H), 3.83- 3.72 (m, 1H), 3.71(s, 3H), 2.88 (qd, J = 17.0, 7.6 Hz, 1H), 2.48-2.35 (m, 2H), 2.25 (s,3H), 1.94 (dq, J = 12.5, 6.4 Hz, 2H). 215 S-isomer

CF₃ H CN R¹² = CH₃ R¹³ = OCH₃ 513.1 ¹H NMR (500 MHz, MeOD) δ 7.61 (s,1H), 7.58 (s, 1H), 7.54-7.41 (m, 1H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H),7.22 (s, 1H), 7.03 (d, J = 9.4 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.89(d, J = 8.4 Hz, 1H), 4.32 (s, 2H), 4.10-4.03 (m, 2H), 3.86 (s, 2H),3.67-3.55 (m, 1H), 2.40-2.27 (m, 2H), 2.27-2.23 (m, 1H), 2.22 (s, 2H),2.10-2.00 (m, 2H) 216 S-isomer

CF₃ H CN R¹² = OCH₃ R¹³ = OCH₃ 529.1 217 S-isomer

CF₃ H CN R¹² = CH₃ R¹³ = CH₃ 497.1 ¹H NMR (500 MHz, MeOD) δ 7.61 (s,1H), 7.49-7.43 (m, 2H), 7.35-7.23 (m, 3H), 6.99-6.94 (m, 2H), 4.32 (s,2H), 4.06 (t, J = 5.9 Hz, 2H), 3.61 (s, 2H), 2.38-2.33 (m, 2H),2.31-2.28 (m, 1H), 2.09-2.01 (m, 2H) 218 S-isomer

CF₃ H CN R¹² = F R¹³ = OCH₃ 517.1 ¹H NMR (500 MHz, MeOD) δ 7.49-7.43 (m,3H), 7.40 (dd, J = 11.9, 2.0 Hz, 1H), 7.14 (t, J = 8.4 Hz, 1H), 7.00-6.93 (m, 2H), 4.32 (s, 2H), 4.05 (t, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.61(d, J = 3.0 Hz, 2H), 2.39-2.27 (m, 2H), 2.09-2.01 (m, 2H) 219 S-isomer

CF₃ H CN R¹² = F R¹³ = CH₃ 501.1 ¹H NMR (500 MHz, MeOD) δ 7.49-7.43 (m,2H), 7.39- 7.32 (m, 1H), 7.30-7.21 (m, 2H), 7.00-6.93 (m, 2H), 4.29 (s,1H), 4.08-4.04 (m, 2H), 3.60 (d, J = 2.0 Hz, 2H), 2.35 (d, J = 5.4 Hz,1H), 2.32- 2.28 (m, 1H), 2.09-2.00 (m, 2H) 220 S-isomer

CF₃ H CN R¹¹ = F R¹³ = Cl 521.0 ¹H NMR (500 MHz, MeOD) δ 7.48-7.43 (m,2H), 7.36- 7.28 (m, 3H), 7.00-6.95 (m, 2H), 4.07 (t, J = 5.9 Hz, 2H),3.59 (q, J = 1.0 Hz, 2H), 2.40- 2.28 (m, 2H), 2.10-2.02 (m, 2H) 221S-isomer

CF₃ H CN R¹² = CH₃ R¹³ = Cl 517.1 ¹H NMR (500 MHz, MeOD) δ 7.61 (s, 1H),7.58 (s, 1H), 7.54-7.41 (m, 1H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 7.22(s, 1H), 7.03 (d, J = 9.4 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 4.32 (s, 2H), 4.10-4.03 (m, 2H), 3.86 (s, 2H), 3.67-3.55(m, 1H), 2.40-2.27 (m, 2H), 2.27-2.23 (m, 1H), 2.22 (s, 2H), 2.10-2.00(m, 2H) 222 S-isomer

CF₃ H CN R¹² = Cl R¹³ = Cl 539.0 223 S-isomer

CF₃ H CN R¹¹ = Cl R¹³ = OCH₃ 532.8 224 S-isomer

CF₃ H CN R¹³ = CN 493.9 225 S-isomer

CF₃ H CN R¹³ = NHSO₂CH₃ 562.1 226 S-isomer

CF₃ H CN R¹¹ = Cl R¹³ = OCH₂CH₃ 547.1 ¹H NMR (500 MHz, MeOD) δ 7.61-7.58(m, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.06- 7.00 (m, 2H), 7.00-6.95 (m,2H), 6.89 (dd, J = 8.4, 2.5 Hz, 1H), 4.11-4.04 (m, 4H), 3.66 (d, J =18.3 Hz, 1H), 3.43 (d, J = 18.3 Hz, 1H), 2.40-2.28 (m, 2H), 2.10- 2.02(m, 2H), 1.45-1.39 (m, 3H) 227 Rac

CF₃ H CN R¹³ = CH₃ 471.2 228 Rac

CF₃ H

R¹³ = CH₃ 609.2 7.86 (s, 1H), 7.66 (s, 1H), 7.37 (d, J = 8.25 Hz, 2H),7.26 (d, J = 9.08 Hz, 2H), 7.21 (d, J = 7.98 Hz, 2H), 6.82 (d, J = 9.08Hz, 2H), 4.18 (t, J = 6.88 Hz, 2H), 3.76 (s, 3H), 3.58 (d, J = 17.33 Hz,1H), 3.35 (d, J = 17.33 Hz, 1H), 2.34 (s, 3H), 2.13 (m, 2H), 1.89 (m,2H), 1.57 (m, 2H), 1.35 (m, 2H). 229 Rac

CF₃ H

R¹³ = CH₃ 595.2 230 Rac

CF₃ H CN R¹³ = CH₃ 434.0 231 S-isomer

CF₃ H

R¹³ = CH₃ 581.4 ¹H NMR (500 MHz, DMSO- d₆) δ 10.43 (s, 1H), 9.23 (s,1H), 7.54 (d, J = 8.80 Hz, 2H), 7.48 (d, J = 1.65 Hz, 1H), 7.29 (d, J =7.98 Hz, 2H), 7.15 (d, J = 7.98 Hz, 2H), 7.00 (d, J = 8.80 Hz, 2H), 6.34(d, J = 1.93 Hz, 1H), 4.07 (t, J = 6.05 Hz, 2H), 3.67 (s, 3H), 3.48 (d,J = 17.06 Hz, 1H), 3.39 (d, J = 17.06 Hz, 1H), 2.43 (m, 2H), 2.27 (s,3H), 1.95 (m, 2H). 232 S-isomer

CF₃ H

R¹³ = CH₃ 609.1 8.13 (d, J = 9.63 Hz, 1H), 7.54 (d, J = 8.80 Hz, 2H),7.26 (d, J = 8.25 Hz, 2H), 7.23 (d, J = 9.63 Hz, 1H), 7.17 (d, J = 7.99Hz, 2H), 6.99 (d, J = 9.08 Hz, 2H), 4.07 (t, J = 6.05 Hz, 2H), 4.01 (s,3H), 3.67 (d, J = 17.33 Hz, 1H), 3.53 (d, J = 17.06 Hz, 1H), 2.37 (m,2H), 2.29 (s, 3H), 2.03 (m, 2H). 233 S-isomer

CF₃ H

R¹³ = CH₃ 479.8 234 S-isomer

CF₃ H

R¹³ = Br 589.9 7.54 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.97(dd, J = 8.7, 2.3 Hz, 4H), 6.85 (br. s., 1H), 4.04 (t, J = 5.8 Hz, 2H),3.69-3.59 (m, 1H), 3.56-3.46 (m, 1H), 2.40- 2.26 (m, 2H), 2.08 (dd, J =9.4, 6.1 Hz, 2H). 235 S-isomer

CF₃ H

¹H NMR (500 MHz, DMSO) δ 9.55 (br. s., 1H), 7.62 (d, J = 8.8 Hz, 2H),7.02 (d, J = 8.8 Hz, 2H), 6.98-6.92 (m, 2H), 6.87 (d, J = 8.3 Hz, 2H),4.07 (t, J = 6.1 Hz, 2H), 3.80-3.61 (m, 2H), 2.46- 2.29 (m, 2H),2.00-1.90 (m, 2H), 1.89-1.79 (m, 1H), 1.00-0.88 (m, 2H), 0.69- 0.54 (m,2H). 236 S-isomer

CF₃ H

578.0 ¹H NMR (500 MHz, DMSO) δ 9.42 (br. s., 1H), 8.47 (d, J = 2.5 Hz,1H), 7.73 (d, J = 1.1 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.64 (d, J =8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.53(d, J = 1.9 Hz, 1H), 4.08 (t, J = 6.2 Hz, 2H), 3.78-3.63 (m, 2H), 2.46-2.34 (m, 2H), 2.02-1.86 (m, 2H). 237 S-isomer

CF₃ H

554.0 ¹H NMR (500 MHz, DMSO) δ 9.42 (br. s., 1H), 7.62 (d, J = 8.5 Hz,2H), 7.02 (d, J = 8.8 Hz, 2H), 6.97 (s, 1H), 6.68 (d, J = 8.5 Hz, 1H),6.59 (d, J = 8.3 Hz, 1H), 4.50 (t, J = 8.7 Hz, 2H), 4.07 (t, J = 6.2 Hz,2H), 3.65 (br. s., 2H), 3.06 (t, J = 8.7 Hz, 2H), 2.47- 2.34 (m, 2H),2.00-1.89 (m, 2H). 238 S-isomer

CF₃ H

555.1 ¹H NMR (500 MHz, DMSO) δ 9.41 (br. s., 1H), 7.61 (d, J = 8.3 Hz,2H), 7.01 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.52 (d, J =8.8 Hz, 2H), 4.06 (t, J = 5.9 Hz, 2H), 3.75-3.55 (m, 2H), 2.89 (s, 6H),2.42 (dd, J = 16.5, 11.0 Hz, 2H), 2.02-1.84 (m, 2H). 239 S-isomer

CF₃ H

R¹³ = CH₃ 593.3 ¹H NMR (400 MHz, MeOD) δ 7.52 (d, J = 8.8 Hz, 2H),7.24-7.15 (m, 4H), 6.96 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 6.1 Hz, 2H),3.97 (s, 2H), 3.67 (d, J = 16.9 Hz, 1H), 3.43 (d, J = 16.9 Hz, 1H), 2.93(s, 3H), 2.44-2.28 (m, 5H), 2.09-1.96 (m, 2H). 240 S-isomer

CF₃ H

R¹³ = OCH₃ 514.3 ¹H NMR (400 MHz, MeOD) δ 7.65 (d, J = 9.0 Hz, 2H),7.13-7.08 (m, 2H), 6.97- 6.93 (m, 2H), 6.84-6.78 (m, 2H), 4.57 (q, J =8.4 Hz, 2H), 3.75 (s, 3H), 3.72 (d, J = 2.4 Hz, 2H). 241 S-isomer

CF₃ H

R¹³ = OCH₃ 528.3 ¹H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.8 Hz, 2H), 7.03(d, J = 9.0 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H),4.25 (t, J = 6.1 Hz, 2H), 3.76 (s, 3H), 3.71 (d, J = 1.5 Hz, 2H),2.77-2.63 (m, 2H). 242 S-isomer

CF₃ H

R¹³ = OCF₃ 582.2 ¹H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.8 Hz, 2H),7.23-7.17 (m, 2H), 7.14- 7.09 (m, 2H), 7.08-7.02 (m, 2H), 4.26 (t, J =6.2 Hz, 2H), 3.83-3.66 (m, 2H), 2.77- 2.63 (m, 2H). 243 S-isomer

CF₃ H

R¹³ = OCF₃ 596.3 ¹H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.8 Hz, 2H),7.22-7.17 (m, 2H), 7.15- 7.09 (m, 2H), 7.06-7.00 (m, 2H), 4.08 (t, J =6.1 Hz, 2H), 3.82-3.65 (m, 2H), 2.44- 2.30 (m, 2H), 2.09-1.99 (m, 2H).244 S-isomer

CF₃ H

R¹³ = OCH₃ 556.3 ¹H NMR (400 MHz, MeOD) δ 7.58 (d, J = 8.8 Hz, 2H), 7.00(d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H),4.04 (t, J = 6.1 Hz, 2H), 3.76 (s, 3H), 3.70 (d, J = 1.3 Hz, 2H),2.31-2.17 (m, 2H), 1.92-1.83 (m, 2H), 1.80- 1.70 (m, 2H). 245 S-isomer

CF₃ H

R¹³ = OCHCF₂ 592.1 ¹H NMR (400 MHz, MeOD) δ 7.59 (d, J = 8.6 Hz, 2H),7.05 (s, 4H), 7.02 (d, J = 9.0 Hz, 2H), 6.87 (t, J = 74.6 Hz, 1H), 4.04(t, J = 6.1 Hz, 2H), 3.74, 3.70 (ABq, J = 18.0 Hz, 2H), 2.31-2.17 (m,2H), 1.92-1.84 (m, 2H), 1.80-1.70 (m, 2H) 246 S-isomer

CF₃ H

R¹³ = CH₃ 582.3 ¹H NMR (400 MHz, MeOD) δ 8.18 (s, 1H), 7.56 (d, J = 8.8Hz, 2H), 7.25-7.19 (m, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 9.0Hz, 2H), 4.09 (s, 3H), 4.07-4.03 (m, 2H), 3.71 (d, J = 16.9 Hz, 1H),3.48 (d, J = 16.9 Hz, 1H), 2.44-2.31 (m, 2H), 2.28 (s, 3H), 2.08-1.98(m, 2H). 247 S-isomer

CF₃ H

R¹³ = OCH₃ 570.1 ¹H NMR (400 MHz, MeOD) δ 7.57 (d, J = 8.8 Hz, 2H),7.03-6.92 (m, 4H), 6.84- 6.79 (m, 2H), 4.02 (t, J = 6.3 Hz, 2H), 3.76(s, 3H), 3.70 (d, J = 1.5 Hz, 2H), 2.25- 2.11 (m, 2H), 1.87-1.77 (m,2H), 1.69-1.53 (m, 4H). 248 S-isomer

CF₃ H

R¹³ = OCHCF₂ 606.3 ¹H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.8 Hz, 2H),7.08 (s, 4H), 7.05-7.01 (m, J = 9.0 Hz, 2H), 6.90 (t, J = 73.7 Hz, 1H),4.05 (t, J = 6.2 Hz, 2H), 3.76, 3.73 (ABq, J = 18.5 Hz, 2H), 2.28-2.14(m, 2H), 1.89-1.81 (m, 2H), 1.72-1.56 (m, 4H) 249 S-isomer

CF₃ H

R¹³ = CH₃ 595.3 ¹H NMR (400 MHz, MeOD) δ 7.62-7.53 (m, 3H), 7.51- 7.45(m, 1H), 7.27-7.09 (m, 6H), 7.01-6.95 (m, 2H), 4.07 (t, J = 6.1 Hz, 2H),3.71 (d, J = 16.9 Hz, 1H), 3.48 (d, J = 16.9 Hz, 1H), 2.43-2.29 (m, 5H),2.08-1.98 (m, 2H). 250 S-isomer

CF₃ H

R¹³ = CH₃ 543.4 8.35 (br. s., 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.18-7.13(m, 2H), 7.11-7.06 (m, 2H), 6.96-6.90 (m, 2H), 6.30 (s, 1H), 4.03 (t, J= 5.9 Hz, 2H), 3.61 (d, J = 17.2 Hz, 1H), 3.38 (d, J = 17.4 Hz, 1H),2.41-2.25 (m, 8H), 2.11- 2.02 (m, 2H). 251 S-isomer

CF₃ H

R¹³ = OCHCF₂ 645.4 ¹H NMR (400 MHz, MeOD) δ 7.52 (d, J = 8.8 Hz, 2H),7.35 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.0 Hz,2H), 7.04-6.63 (m, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.98 (s, 2H), 3.69 (d,J = 16.9 Hz, 1H), 3.45 (d, J = 16.9 Hz, 1H), 2.93 (s, 3H), 2.44-2.29 (m,2H), 2.09-1.98 (m, 2H). 252 S-isomer

CF₃ H

R¹³ = OCH₃ 623.3 ¹H NMR (400 MHz, MeOD) δ 7.51 (d, J = 8.8 Hz, 2H), 7.30(d, J = 9.0 Hz, 2H), 6.98-6.88 (m, 4H), 4.02 (t, J = 6.1 Hz, 2H), 3.99(s, 2H), 3.79 (s, 3H), 3.66 (d, J = 16.9 Hz, 1H), 3.44 (d, J = 16.7 Hz,1H), 2.97 (s, 3H), 2.30-2.16 (m, 2H), 1.90- 1.81 (m, 2H), 1.79-1.69 (m,2H). 253 S-isomer

CF₃ H

R¹³ = CH₃ 545.4 ¹H NMR (400 MHz, MeOD) δ 7.56 (d, J = 8.8 Hz, 2H),7.22-7.17 (m, 4H), 7.03- 6.96 (m, 2H), 4.09 (t, J = 6.1 Hz, 2H), 4.02(q, J = 6.8 Hz, 1H), 3.66 (d, J = 17.2 Hz, 1H), 3.47 (d, J = 16.9 Hz,1H), 2.46-2.32 (m, 5H), 2.10-2.00 (m, 2H), 1.19 (d, J = 6.8 Hz, 3H). 254S-isomer

CF₃ H

R¹³ = OCHCF₂ 596.2 ¹H NMR (400 MHz, MeOD) δ 7.53 (d, J = 8.8 Hz, 2H),7.39-7.33 (m, 2H), 7.11 (d, J = 8.6 Hz, 2H), 7.00-6.95 (m, 2H),7.02-6.63 (m, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.65 (d, J = 16.9 Hz, 1H),3.42 (d, J = 16.7 Hz, 1H), 2.96 (q, J = 7.3 Hz, 2H), 2.43-2.28 (m, 2H),2.07-1.97 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 255 S-isomer

CF₃ H

R¹³ = CH₃ 545.3 ¹H NMR (400 MHz, MeOD) δ 7.53 (d, J = 8.8 Hz, 2H),7.29-7.22 (m, 2H), 7.21- 7.14 (m, 2H), 6.97 (d, J = 9.0 Hz, 2H), 4.06(t, J = 6.2 Hz, 2H), 3.66 (d, J = 16.9 Hz, 1H), 3.45 (d, J = 16.7 Hz,1H), 3.07 (q, J = 7.2 Hz, 2H), 2.45-2.29 (m, 5H), 2.02 (dd, J = 10.2,5.8 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H). 256 S-isomer

CF₃ H CN R¹¹ = F R¹³ = CH₃ 501.1 ¹H NMR (400 MHz, MeOD) δ 1.96-2.13 (m,2 H) 2.24- 2.39 (m, 2 H) 2.41 (s, 3 H) 3.49-3.68 (m, 2 H) 3.75 (s, 1 H)4.06 (t, J = 5.95 Hz, 2 H) 4.33 (s, 1 H) 6.97 (d, J = 1.00 Hz, 2 H)7.00-7.14 (m, 2 H) 7.24 (t, J = 7.68 Hz, 1 H) 7.45 (d, J = 1.00 Hz, 2 H)7.61 (s, 1 H) 257 S-isomer

CF₃ H CN R¹³ = NHCO₂Me 541.5 258 S-isomer

CF₃ H CN R¹² = Cl R¹³ = OCH₃ 533.1 259 S-isomer

CF₃ H CN R¹² = Cl R¹³ = CH₃ [M − H] 515.0 ¹H NMR (500 MHz, MeOD) δ 2.05(m, J = 9.90, 5.90 Hz, 2 H) 2.22-2.41 (m, 2 H) 2.24-2.42 (m, 2 H) 2.43(s, 2 H) 3.62 (br. s., 1 H) 4.06 (t, J = 5.95 Hz, 2 H) 4.29-4.48 (m, 2H)6.98 (d, J = 8.92 Hz, 1 H) 7.40 (br. s., 1 H) 7.47 (d, J = 8.42 Hz, 1 H)7.54 (s, 1 H) 7.63 (br. s., 1 H) 260 S-isomer

CF₃ H CN R¹³ = CH₂OCH₃ 513.1 ¹H NMR (500 MHz, MeOD) δ 1.97-2.11 (m, 2 H)2.33 (m, J = 5.40 Hz, 2 H) 3.43 (s, 3 H) 3.63 (s, 2 H) 4.06 (t, J = 5.95Hz, 2 H) 4.53 (s, 2 H) 6.97 (d, J = 1.00 Hz, 2 H) 7.47 (d, J = 8.42 Hz,4 H) 7.55 (d, J = 7.93 Hz, 2 H) 7.60 (s, 1 H) 261 S-isomer

CF₃ H CN R¹² = F R¹³ = OCF₃ 571.1 262 S-isomer

CF₃ H CN R¹² = OCH₃ R¹³ = CH₃ 513.1 ¹H NMR (500 MHz, MeOD) δ 1.95-2.12(m, 2 H) 2.25 (s, 3 H) 2.27-2.44 (m, 2 H) 3.63 (d, J = 2.48 Hz, 2 H)3.87 (s, 3 H) 4.05 (t, J = 5.95 Hz, 2 H) 6.97 (m, J = 8.92 Hz, 2 H) 7.08(d, J = 1.49 Hz, 1 H) 7.24 (s, 1 H) 7.47 (m, J = 8.92 Hz, 2 H) 7.60 (s,1 H) 263 S-isomer

CF₃ H CN R¹² = Cl R¹³ = OCH₂CH₃ 547.1 ¹H NMR (500 MHz, MeOD) δ 1.49 (t,J = 6.94 Hz, 3 H) 1.95-2.12 (m, 2 H) 2.23- 2.41 (m, 2 H) 3.60 (s, 2 H)4.05 (t, J = 5.95 Hz, 2 H) 4.19 (q, J = 6.90 Hz, 2 H) 6.96 (d, J = 9.41Hz, 2 H) 7.08 (d, J = 8.92 Hz, 1 H) 7.46 (d, J = 8.92 Hz, 2 H) 7.55 (dd,J = 1.00 Hz, 1 H) 7.60 (s, 1 H) 7.64 (d, J = 1.00 Hz, 1 H) 264 S-isomer

CF₃ H CN R¹² F R¹³ = OCH₂CH₃ [M − H] 529.1 ¹H NMR (500 MHz, MeOD) δ 1.47(t, J = 7.18 Hz, 3 H) 1.95-2.12 (m, 2 H) 2.33 (s, 2 H) 4.06 (t, J = 5.95Hz, 2 H) 4.19 (q, J = 6.90 Hz, 2 H) 6.97 (d, J = 8.92 Hz, 2 H) 7.12 (t,J = 1.00 Hz, 1 H) 7.37-7.53 (m, 4 H) 7.62 (s, 1H) 265 S-isomer

CF₃ H

R¹³ = CH₃ 607.1 ¹H NMR (500 MHz, MeOD) δ 7.88 (dd, J = 8.0, 1.4 Hz, 1H),7.55 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz,2H), 7.05-6.97 (m, 3H), 6.89 (d, J = 7.4 Hz, 1H), 6.85-6.80 (m, 1H),4.07 (t, J = 6.1 Hz, 2H), 3.68 (s, 3H), 3.63 (d, J = 17.3 Hz, 1H), 3.51(d, J = 17.3 Hz, 1H), 2.43-2.32 (m, 2H), 2.31 (s, 3 H), 2.07-1.98 (m,2H). 266 S-isomer

CF₃ H

R¹³ = CH₃ 544.1 ¹H NMR (500 MHz, MeOD) δ 7.50 (dd, J = 12.7, 2.5 Hz,1H), 7.45-7.38 (m, 1H), 7.18 (t, J = 8.7 Hz, 1H), 7.12- 7.06 (m, 2H),6.89 (d, J = 8.2 Hz, 2H), 4.16 (t, J = 6.1 Hz, 2H), 3.74 (d, J = 17.8Hz, 1H), 3.68 (d, J = 17.8 Hz, 1H), , 2.52-2.32 (m, 2H), 2.29 (s, 3H),2.13-1.98 (m, 2H). 267 S-isomer

CF₃ H

R¹³ = CH₃ 526.2 268 S-isomer

CF₃ H

R¹³ = CH₃ 544.2 ¹HNMR (500 MHz, DMSO- d₆) δ 9.58 (s, 1H), 7.59 (t, J =9.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.99-6.92 (m, 2H), 6.89 (d, J =8.1 Hz, 2H), 4.11 (t, J = 6.1 Hz, 2H), 3.81 (d, J = 17.7 Hz, 1H), 3.73(d, J = 17.8 Hz, 1H), 2.49-2.30 (m, 2H), 2.25 (s, 3H), 2.03-1.78 (m,2H). 269 S-isomer

CF₃ H CN R¹³ = CH₃ 483.2 ¹HNMR (400 MHz, MeOD) δ 8.18 (s, 1H), 7.56 (d,J = 8.8 Hz, 2H), 7.25-7.19 (m, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.98 (d, J= 9.0 Hz, 2H), 4.09 (s, 3H), 4.07-4.03 (m, 2H), 3.71 (d, J = 16.9 Hz,1H), 3.48 (d, J = 16.9 Hz, 1H), 2.44-2.31 (m, 2H), 2.28 (s, 3H),2.08-1.98 (m, 2H). 270 R-isomer

CF₃ H

R¹³ = CH₃ 554.1 ¹H NMR (400 MHz, MeOD) δ 7.51 (d, J = 8.8 Hz, 2H), 7.30(d, J = 9.0 Hz, 2H), 6.98-6.88 (m, 4H), 4.02 (t, J = 6.1 Hz, 2H), 3.99(s, 2H), 3.79 (s, 3H), 3.66 (d, J = 16.9 Hz, 1H), 3.44 (d, J = 16.7 Hz,1H), 2.97 (s, 3H), 2.30-2.16 (m, 2H), 1.90- 1.81 (m, 2H), 1.79-1.69 (m,2H). 271 S-isomer

CF₃ H

R¹³ = CH₂CF₃ 594.1 ¹H NMR (500 MHz, 1:1 MeOD/CDCl₃) δ 7.52 (d, J = 8.8Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.96 (dd, J = 8.4, 2.1 Hz, 4H), 4.04(t, J = 6.1 Hz, 2H), 3.73-3.64 (m, 1H), 3.60-3.49 (m, 1H), 3.35 (d, J =10.7 Hz, 2H), 2.39-2.23 (m, 2H), 2.13-1.91 (m, 2H). 272 S-isomer

CF₃ H

R¹³ = CH₃ 540.3 273 S-isomer

CF₃ H

R¹³ = CH₃ 608.2 1.98-2.11 (m, 2H), 2.29 (s, 3H), 2.33-2.49 (m, 2H),3.71-3.47 (m, 2H), 3.91 (s, 3H), 4.20-4.02 (m, 2H), 6.95-7.03 (m, 2H),7.15 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.8 Hz,2H), 7.86 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 1.4 Hz, 1H). 274 S-isomer

CF₃ H

R¹³ = OCHF₂ 624.1 ¹H NMR (500 MHz, DMSO- d₆) δ 9.63 (s, 1H), 7.58 (t, J= 9.3 Hz, 1H), 7.43-6.98 (m, 5H), 6.92 (d, J = 12.1 Hz, 2H), 4.03 (t, J= 6.4 Hz, 2H), 3.80 (d, J = 17.8 Hz, 1H), 3.76 (d, J = 17.9 Hz, 1H),2.37-2.14 (m, 2H), 1.83-1.66 (m, 2H), 1.63- 1.32 (m, 4H). 275 S-isomer

CF₃ H

R¹³ = OCHF₂ 630.2 ¹H NMR (400 MHz, MeOD) δ 8.75 (br. s., 2H), 7.87 (br.s., 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.12 (d, J= 8.6 Hz, 2H), 7.04-6.62 (m, 3H), 4.08 (t, J = 5.8 Hz, 2H), 3.75 (br.s., 1H), 3.52 (d, J = 16.9 Hz, 1H), 2.45-2.29 (m, 2H), 2.09-1.99 (m,2H). 276 S-isomer

CF₃ H

608.2 ¹H NMR (500 MHz, MeOD) δ 7.83-7.66 (m, 3H), 7.61 (s, 2H),7.56-7.43 (m, 3H), 7.01 (d, J = 8.6 Hz, 1H), 6.85- 6.67 (m, 2H), 4.05(d, J = 18.0 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.76 (d, J = 17.9 Hz,1H), 2.05-2.20 (m, 2H), 1.91-1.72 (m, 2H), 1.74- 1.45 (m, 4H). 277S-isomer

CF₃ H

567.1 ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ 7.54 (d, J = 8.4 Hz, 2H), 7.16(d, J = 7.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H),4.07 (t, J = 5.9 Hz, 2H), 3.79- 3.66 (m, 1H), 3.63-3.50 (m, 1H), 2.49(d, J = 6.9 Hz, 2H), 2.40-2.25 (m, 2H), 2.13-1.97 (m, 2H), 0.97- 0.82(m, 1H), 0.58-0.45 (m, 2H), 0.16 (q, J = 5.0 Hz, 2H). 278 S-isomer

CF₃ H

R¹³ = CH₃ 558.2 ¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ 7.43 (t, J = 9.17 Hz,1H), 7.02 (d, J = 7.93 Hz, 2H), 6.87 (d, J = 7.93 Hz, 2H), 6.75 (dd, J =2.48, 8.92 Hz, 1H), 6.71 (dd, J = 2.23, 14.61 Hz, 1H), 3.99 (t, J = 5.95Hz, 2H), 3.87 (d, J = 17.83 Hz, 1H), 3.61 (d, J = 17.83 Hz, 1H), 2.26(s, 3H), 2.11-2.21 (m, 2H), 1.80-1.89 (m, 2H), 1.69-1.78 (m, 2H). 279S-isomer

CF₃ H

R¹³ = CH₃ 573.2 7.79 (br. s., 1H), 7.46-7.38 (m, 7H), 7.22-7.17 (m, 2H),7.15-7.10 (m, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.69 (br. s., 1H), 5.07 (s,2H), 3.82 (br. s., 2H), 3.63 (d, J = 17.2 Hz, 1H), 3.37 (d, J = 17.2 Hz,1H), 2.95 (s, 3H), 2.36 (s, 3H). 280 S-isomer

CF₃ H

R¹³ = OCHF₂ 630.2 281 S-isomer

CF₃ H

R¹³ = CH₃ 582.2 ¹H NMR (500 MHz, MeOD) δ 7.56 (d, J = 8.92 Hz, 2H), 7.30(d, J = 8.42 Hz, 2H), 7.10 (d, J = 7.93 Hz, 2H), 6.97 (d, J = 8.92 Hz,2H), 6.37 (s, 1H), 4.06 (m, 2H), 3.59 (d, J = 17.83 Hz, 1H), 3.43 (d, J= 17.34 Hz, 1H), 2.32 (m, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.06 (m, 2H).282 S-isomer

CF₃ H

R¹³ = CH₃ 651.2 ¹H NMR (500 MHz, MeOD) δ 7.61 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 7.15 (d, J = 5.9 Hz, 4H), 6.93 (d, J = 8.9 Hz, 2H), 4.33 (br.s., 1H), 4.07- 4.02 (m, 2H), 4.02-3.94 (m, 4H), 3.67-3.56 (m, 1H),3.37-3.34 (m, 1H), 2.94- 2.78 (m, 2H), 2.33 (s, 5H), 2.09-2.00 (m, 2H),1.22 (d, J = 1.5 Hz, 6H). 283 S-isomer

CF₃ H

R¹³ = OCH₂CH₃ 602.2 ¹H NMR (500 MHz, DMSO- d₆) δ 9.39 (s, 1H), 7.56 (t,J = 9.3 Hz, 1H), 6.92 (t, J = 8.6 Hz, 4H), 6.81 (d, J = 8.8 Hz, 2H),4.03 (t, J = 6.4 Hz, 2H), 3.99 (q, J = 6.9 Hz , 2H), 3.82 (d, J = 17.3Hz, 1H), 3.69 (d, J = 17.7 Hz, 1H), 2.34-2.15 (m, 2H), 1.85- 1.70 (m,2H), 1.65-1.42 (m, 4H), 1.29 (t, J = 6.9 Hz, 3H). 284 S-isomer

CF₃ H

R¹³ = CH₂CF₃ 640.1 ¹H NMR (500 MHz, DMSO- d₆) δ 9.36 (w, 1H), 7.59 (t, J= 9.3 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 7.07-6.74 (m, 4H), 4.03 (t, J =6.4 Hz, 2H), 3.76 (d, J = 17.4 Hz, 1H), 3.70 (d, J = 17.7 Hz, 1H), 3.58(dd, J = 23.3, 11.7 Hz, 2H), 2.33-2.16 (m, 2H), 1.86-1.68 (m, 2H),1.545- 1.60 (m, 4H). 285 S-isomer

CF₃ H

R¹³ = CH₃ 484.1 ¹H NMR (500 MHz, DMSO- d₆) δ 9.58-9.48 (m, 1H),7.65-7.55 (m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.04-6.97 (m, 2H),6.94-6.85 (m, 2H), 4.06 (s, 2H), 3.69 (s, 2H), 2.24 (s, 3H), 1.63 (q, J= 6.6 Hz, 2H), 1.35-1.08 (m, 1H), 0.94-0.77 (m, 1H), 0.51- 0.38 (m, 2H),0.16-0.06 (m, 2H) 286 S-isomer

CF₃ H

R¹¹ = F R¹³ = CH₃ 544.2 ¹H NMR (500 MHz, DMSO- d₆) δ 7.62 (d, J = 8.80Hz, 2H), 7.02 (d, J = 8.80 Hz, 2H), 7.01 (m, 1H), 6.98 (t, J = 7.98 Hz,1H), 6.93 (d, J = 11.55 Hz, 1H), 4.08 (t, J = 6.93 Hz, 2H), 3.68 (d, J =18.16 Hz, 1H), 3.62 (d, J = 17.88 Hz, 1H), 2.42 (m, 2H), 2.28 (s, 3H),1.95 (m, 2H). 287 S-isomer

CF₃ H

R¹³ = CH₃ 568.2 ¹H NMR (500 MHz, DMSO- d₆) δ 9.47 (s, 1H), 7.49 (s, 1H),7.45 (d, J = 8.80 Hz, 1H), 7.07 (d, J = 7.98 Hz, 2H), 6.98 (d, J = 8.80Hz, 1H), 6.89 (d, J = 8.25 Hz, 2H), 4.00 (t, J = 6.19 Hz, 2H), 3.66 (s,2H), 2.24 (s, 3H), 2.20-2.32 (m, 2H), 2.17 (s, 3H), 1.71-1.80 (m, 2H),1.47-1.61 (m, 4H). 288 S-isomer

CF₃ H

R¹³ = CH₃ 520.0 ¹H NMR (500 MHz, DMSO- d₆) δ 9.67 (s, 1H), 8.15 (d, J =4.1 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 4.1 Hz, 1H), 6.98(d, J = 8.8 Hz, 2H), 4.03 (t, J = 6.2 Hz, 2H), 3.98 (d, J = 17.6 Hz,1H), 3.62 (d, J = 17.3 Hz, 1H), 2.45-2.33 (m, 2H), 2.31- 2.23 (m, 1H),1.94-1.79 (m, 2H), 1.23-1.11 (m, 2H), 0.87-0.77 (m, 2H). 289 S-isomer

CF₃ H

R¹³ = CH₃ 444.1 7.17 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.84(s, 1H), 3.39 (AB quartet, J = 18.7 Hz, 2H), 2.36 (s, 3H), 2.13 (d, J =6.6 Hz, 2H), 1.77-1.60 (m, 5H), 1.55-1.42 (m, 1H), 1.29- 0.88 (m, 5H).290 S-isomer

CF₃ H

R¹³ = CH₃ 468.1 7.36-7.27 (m, 5H), 7.18 (s, 1H), 7.13 (d, J = 7.9 Hz,2H), 7.01 (d, J = 8.1 Hz, 2H), 4.57 (AB quartet, J = 11.7 Hz, 2H), 4.22(s, 2H), 3.39 (AB quartet, J = 18.9 Hz, 2H), 2.34 (s, 3H). 291 S-isomer

CF₃ H

R¹³ = CH₃ 430.1 7.19 (d, J = 7.9 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.59(s, 1H), 3.38 (AB quartet, J = 18.9 Hz, 2H), 2.49-2.41 (m, 1H), 2.38 (s,3H), 1.81-1.72 (m, 2H), 1.65 (dd, J = 5.9, 2.4 Hz, 2H), 1.54-1.40 (m, J= 12.5, 8.9, 8.9, 8.9 Hz, 3H), 1.38-1.28 (m, 3H). 292 Rac

CF₃ H

R¹³ = CH₃ 394.5 293 S-isomer

CF₃ H

R¹³ = CH₃ 432.1 7.19 (d, J = 7.9 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.67(s, 1H), 3.38 (AB quartet, J = 18.9 Hz, 2H), 2.37 (s, 3H), 2.23 (t, J =7.0 Hz, 2H), 1.51 (quin, J = 7.3 Hz, 2H), 1.40-1.22 (m, 6H), 0.87 (t, J= 6.8 Hz, 3H). 294 S-isomer

CF₃ H

R¹³ = OCH₃ 468.1 1H NMR (500 MHz, MeOD) δ 7.31-7.15 (m, 5H), 6.96 (d, J= 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H), 3.34 (AB quartet,J = 18.3 Hz, 2H, partially overlapping with solvent), 2.85 (t, J = 7.2Hz, 2H), 2.58 (t, J = 7.4 Hz, 2H). 295 S-isomer

CF₃ H

R¹³ = OCH₃ 434.1 1H NMR (500 MHz, MeOD) δ 7.01 (d, J = 8.9 Hz, 2H), 6.78(d, J = 8.9 Hz, 2H), 3.77 (s, 3H), 3.40 (s, 2H), 2.29 (t, J = 7.4 Hz,2H), 1.69 (dt, J = 13.5, 6.9 Hz, 1H), 1.45 (q, J = 7.4 Hz, 2H), 0.91(dd, J = 6.9, 2.0 Hz, 6H). 296 S-isomer

CF₃ H

R¹¹ = F R¹³ = CH₃ 625.2 ¹H NMR (500 MHz, DMSO- d₆) δ 7.55 (d, J = 8.80Hz, 2H), 7.31 (d, J = 9.08 Hz, 2H), 7.13 (m, 1H), 7.06 (d, J = 11.83 Hz,1H), 7.00 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 7.70 Hz, 1H), 6.80 (d, J =9.08 Hz, 2H), 4.08 (m, 2H), 3.70 (m, 2H), 3.68 (s, 3H), 2.43 (m, 2H),2.27 (s, 3H), 1.95 (m, 2H). 297 S-isomer

CF₃ H

R¹³ = CH₃ 608.1 7.43 (d, J = 8.6 Hz, 2H), 7.20-7.16 (m, 2H), 7.15- 7.10(m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.57 (s, 1H), 5.10 (br. s., 1H), 4.03(t, J = 5.9 Hz, 2H), 3.72 (br. s., 2H), 3.62 (d, J = 17.6 Hz, 1H), 3.38(d, J = 17.8 Hz, 1H), 2.80-2.74 (m, 3H), 2.40- 2.24 (m, 5H), 2.12-2.02(m, 2H) 298 S-isomer

CF₃ H

R¹³ = CH₃ 499.1 7.74 (br. s., 1H), 7.26-7.20 (m, 4H), 5.88 (s, 1H), 3.84(s, 2H), 3.29 (ABq, J = 17.6 Hz, 2H), 2.95 (s, 3H), 2.37 (s, 3H), 2.23(t, J = 7.0 Hz, 2H), 1.57-1.48 (m, 2H), 1.41-1.25 (m, 6H), 0.89 (t, J =6.8 Hz, 3H) 299 S-isomer

CF₃ H

R¹³ = CH₃ 578.1 9.08 (br. s., 1H), 8.77 (d, J = 4.2 Hz, 1H), 8.37 (br.s., 1H), 8.25 (br. s., 1H), 7.65 (br. s., 1H), 7.46 (d, J = 8.8 Hz, 2H),7.19-7.11 (m, 4H), 6.95 (d, J = 9.0 Hz, 2H), 6.88 (s, 1H), 4.04 (t, J =5.9 Hz, 2H), 3.66 (d, J = 17.6 Hz, 1H), 3.43 (d, J = 17.4 Hz, 1H),2.40-2.25 (m, 5H), 2.12-2.03 (m, 2H). 300 S-isomer

CF₃ H

R¹³ = CH₃ 484.2 ¹H NMR (400 MHz, MeOD) δ 9.00 (br. s., 1H), 8.79 (dd, J= 5.3, 1.3 Hz, 1H), 8.46 (d, J = 7.3 Hz, 1H), 7.78 (dd, J = 8.0, 5.4 Hz,1H), 7.33 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 3.38 (s, 2H),2.35-2.27 (m, 5H), 1.60- 1.50 (m, 2H), 1.48-1.38 (m, 2H), 1.35-1.27 (m,4H), 0.93-0.87 (m, 3H). 301 S-isomer

CF₃ H

R¹³ = OCHF₂ 624.2 ¹H NMR (500 MHz, DMSO- d₆) δ 9.53 (s, 1H), 7.65 (dd, J= 13.0, 2.0 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.46-6.88 (m, 6H), 4.11(t, J = 6.3 Hz, 2H), 3.77 (d, J = 17.9 Hz, 1H), 3.72 (d, J = 17.9 Hz,1H), 2.36-2.08 (m, 2H), 1.88-1.71 (m, 2H), 1.67- 1.34 (m, 4H). 302S-isomer

CF₃ H

R¹³ = CH₃ 525.0 ¹HNMR (400 MHz, MeOD) δ 7.50 (d, J = 8.8 Hz, 2H),7.23-7.15 (m, 4H), 6.93 (d, J = 9.0 Hz, 2H), 4.00-3.92 (m, 4H), 3.66 (d,J = 17.2 Hz, 1H), 3.43 (d, J = 16.9 Hz, 1H), 2.93 (s, 3H), 2.32 (s, 3H),1.79 (sxt, J = 7.0 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H). 303 S-isomer

CF₃ H

R¹³ = CH₃ 572.3 304 S-isomer

CF₃ H

608.3 ¹HNMR (500 MHz, DMSO- d₆) δ 9.57 (br. s., 1H), 7.84 (dd, J = 7.84,13.34 Hz, 2H), 7.71-7.77 (m, 2H), 7.67 (d, J = 12.93 Hz, 1H), 7.47-7.57(m, 3H), 7.26 (t, J = 8.94 Hz, 1H), 6.93 (d, J = 8.80 Hz, 1H), 5.56 (d,J = 7.70 Hz, 1H), 4.10 (t, J = 6.19 Hz, 2H), 3.79-3.92 (m, 2H),2.20-2.33 (m, 2H), 1.68-1.83 (m, 2H), 1.45-1.65 (m, 4H). 305 S-isomer

CF₃ H

R¹³ = OCH₂CH₃ 602.3 ¹HNMR (500 MHz, DMSO- d₆) δ 9.38-9.54 (m, 1H), 7.63(d, J = 13.20 Hz, 1H), 7.46 (d, J = 8.80 Hz, 1H), 7.24 (t, J = 8.80 Hz,1H), 6.96 (d, J = 8.53 Hz, 2H), 6.79 (d, J = 8.53 Hz, 2H), 4.09 (t, J =6.33 Hz, 2H), 3.98 (q, J = 6.88 Hz, 2H), 2.20-2.34 (m, 2H), 1.77 (quin,J = 6.81 Hz, 2H), 1.46-1.61 (m, 4H), 1.28 (t, J = 7.02 Hz, 3H). 306S-isomer

CF₃ H

R¹³ = CH₂CF₃ 640.2 ¹HNMR (500 MHz, DMSO- d₆) δ 9.56 (br. s., 1H), 7.65(d, J = 12.93 Hz, 1H), 7.49 (d, J = 8.80 Hz, 1H), 7.20- 7.28 (m, 3H),7.03 (d, J = 7.98 Hz, 2H), 4.10 (t, J = 6.33 Hz, 2H), 3.71-3.81 (m, 2H),3.61 (q, J = 11.55 Hz, 2H), 2.20-2.33 (m, 2H), 1.78 (quin, J = 6.74 Hz,2H), 1.44-1.61 (m, 4H) 307 S-isomer

CF₃ H

R¹³ = OCHF₂ 484.1 7.19 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H),6.78 (br. s., 1H), 6.56 (t, J = 73.1 Hz, 1H), 3.37 (AB quartet, J = 18.9Hz, 2H), 2.24 (t, J = 7.0 Hz, 2H), 1.52 (quin, J = 7.3 Hz, 2H), 1.41-1.21 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H). 308 S-isomer

CF₃ H

R¹³ = OCH₂CH₃ 462.1 7.10 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H),6.72 (s, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.37 (AB quartet, J = 18.9 Hz,2H), 2.22 (t, J = 7.2 Hz, 2H), 1.51 (quin, J = 7.3 Hz, 2H), 1.42 (t, J =7.0 Hz, 3H), 1.39-1.22 (m, 6H), 0.87 (t, J = 6.6 Hz, 3H). 309 S-isomer

CF₃ H

612.1 ¹HNMR (500 MHz, DMSO- d₆) δ 9.52 (br. s., 1H), 7.63 (d, J = 13.20Hz, 1H), 7.46 (d, J = 8.53 Hz, 1H), 7.25 (t, J = 8.94 Hz, 1H), 6.88 (d,J = 7.98 Hz, 1H), 6.83 (s, 1H), 6.58 (d, J = 7.98 Hz, 1H), 4.09 (t, J =6.19 Hz, 2H), 3.64-3.75 (m, 2H), 2.54-2.67 (m, 4H), 2.20-2.34 (m, 2H),1.77 (quin, J = 6.74 Hz, 2H), 1.67 (br. s., 4H), 1.44-1.61 (m, 4H). 310S-isomer

CF₃ H

R¹³ = CH₃ 569.0 ¹HNMR (400 MHz, MeOD) δ 7.56 (d, J = 8.8 Hz, 2H),7.26-7.21 (m, 2H), 7.18- 7.12 (m, 2H), 6.99 (d, J = 9.0 Hz, 2H), 4.07(t, J = 6.2 Hz, 2H), 3.73 (d, J = 17.2 Hz, 1H), 3.51 (d, J = 16.9 Hz,1H), 2.43-2.32 (m, 2H), 2.29 (s, 3H), 2.08-1.98 (m, 2H). 311 S-isomer

CF₃ H

R¹³ = CH₃ 475.1 ¹HNMR (400 MHz, MeOD) δ 7.34 (d, J = 8.1 Hz, 2H), 7.19(d, J = 7.9 Hz, 2H), 3.37 (s, 2H), 2.34-2.26 (m, 5H), 1.53 (d, J = 7.3Hz, 2H), 1.42 (br. s., 2H), 1.34- 1.25 (m, 4H), 0.92-0.86 (m, 3H). 312S-isomer

CF₃ H

R¹³ = OCH₂CH₃ 529.4 7.73 (br. s., 1H), 7.31 (d, J = 8.6 Hz, 2H), 6.92(d, J = 8.8 Hz, 2H), 5.91 (s, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.86 (s,2H), 3.30, 3.28 (ABq, J = 18.3 Hz, 2H), 2.99 (s, 3H), 2.23 (t, J = 7.0Hz, 2H), 1.52 (quin, J = 7.3 Hz, 2H), 1.43 (t, J = 6.9 Hz, 3H), 1.41-1.22 (m, 7H), 0.89 (t, J = 6.9 Hz, 2H). 313 S-isomer

CF₃ H

R¹³ = OCHF₂ 551.0 7.85 (br. s., 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.17 (d,J = 8.6 Hz, 2H), 6.55 (t, J = 72.4 Hz, 1H), 5.97 (s, 1H), 3.84 (s, 2H),3.30, 3.28 (ABq, J = 17.8 Hz, 2H), 2.89 (s, 3H), 2.24 (t, J = 7.0 Hz,2H), 1.52 (dt, J = 14.6, 7.2 Hz, 2H), 1.43-1.23 (m, 6H), 0.89 (t, J =6.8 Hz, 3H). 314 S-isomer

CF₃ H

R¹³ = CH₃ 540.3

What is claimed is:
 1. A compound of Formula (II):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: R¹ is independently selected from the group consistingof: C₁₋₆ alkyl, C₃₋₆ cycloalkyl, —CONHC₄₋₁₈ alkyl, —CONHC₂₋₈ haloalkyl,—CONH(CH₂)₁₋₈ Ph, —(CH₂)_(m)-(phenyl substituted with 1 R^(b) and 0-2R^(g)), and a 5- to 6-membered heteroaryl substituted with 0-1 R^(b) and0-2 R^(g), wherein said heteroaryl is selected from: pyridyl, oxazolyl,thiazolyl and

R² is independently selected from the group consisting of: C₁₋₄ alkyland C₁₋₄ haloalkyl; R³ is independently selected from the groupconsisting of: H and F; R⁴ is independently selected from the groupconsisting of: H and F; R⁶ is independently R^(c) or—(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c); R¹¹ and R¹⁵ are independentlyselected from the group consisting of: H, C₁₋₄ alkyl and halo; R¹² andR¹⁴ are independently selected from the group consisting of: H, halo,C₁₋₄ alkyl and C₁₋₄ alkoxy; R¹³ is independently selected from the groupconsisting of: H, halo, C₁₋₄ alkyl substituted with 0-1 C₁₋₄ alkoxy,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, —(CH₂)_(m)—C₃₋₄cycloalkyl, CN, N(C₁₋₄ alkyl)₂, NHCO₂(C₁₋₄ alkyl), NHSO₂(C₁₋₄ alkyl),pyrazolyl, and morpholinyl; alternatively, R¹² and R¹³, together withthe carbon atoms to which they are attached, combine to form a 5- to6-membered carbocyclic ring or a 5- to 6-membered heterocyclic ringcomprising: carbon atoms and 1-3 heteroatoms selected from N, NR^(e), O,and S; R^(b) is, at each occurrence, independently selected from thegroup consisting of: halo, OH, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl,C₁₋₁₀ haloalkoxy, —O(CH₂)_(s)O(C₁₋₆ alkyl), N(C₁₋₄ alkyl)₂,—CONH(CH₂)₆₋₂₀H, —(CH₂)_(m)(C₃₋₆ cycloalkyl), —(CH₂)_(m)(C₄₋₆cycloalkenyl), —O(CH₂)_(m)(C₃₋₆ cycloalkyl), 4-C₁₋₄ alkoxy-Ph,—O(CH₂)_(m)Ph, morpholinyl, pyridyl, 2-C₁₋₄ alkoxy-pyridin-5-yl,pyrimidinyl, pyrazinyl, and —O-pyrimidinyl; R^(c) is, at eachoccurrence, independently selected from the group consisting of: C₃₋₆cycloalkyl substituted with 0-2 R^(d), C₃₋₆ cycloalkenyl substitutedwith 0-2 R^(d), —(CH₂)_(m)-(phenyl substituted with 0-3 R^(d)), and a 5-to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NR^(e), O, and S; wherein said heterocycle issubstituted with 0-2 R^(d); R^(d) is, at each occurrence, independentlyselected from the group consisting of: halo, OH, CN, NO₂, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, tetrazolyl, OBn and phenylsubstituted with 0-2 Rh; R^(e) is, at each occurrence, independentlyselected from the group consisting of: H, C₁₋₈ alkyl, C₁₋₈ haloalkyl,benzyl optionally substituted with C₁₋₄ alkoxy, CO(C₁₋₄ alkyl) and COBn;R^(f) is, at each occurrence, independently selected from the groupconsisting of: H and C₁₋₄ alkyl; R^(g) and R^(h) are, at eachoccurrence, independently selected from the group consisting of: halo,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; n, at eachoccurrence, is independently 0 or 1; m, at each occurrence, isindependently 0, 1, 2 or 3; s, at each occurrence, is independently 1,2, or 3; and t, at each occurrence, is independently 0 or
 1. 2. Acompound according to claim 1, wherein: R¹ is independently selectedfrom the group consisting of: C₁₋₆ alkyl, —CONHC₄₋₁₈ alkyl,—CONH(CH₂)₁₋₈Ph, and

R⁶ is independently R^(c), OR^(c), —CONHR^(c), or —NHCOR^(c); R¹² isindependently selected from the group consisting of: H, halo, C₁₄ alkyland C₁₄ alkoxy; R¹³ is independently selected from the group consistingof: H, halo, C₁₄ alkyl substituted with 0-1 C₁₋₄ alkoxy, C₁₄ alkoxy,C₁₋₄ haloalkyl, C₁₄ haloalkoxy, —(CH₂)_(m)—C₃₋₄ cycloalkyl, CN, N(C₁₋₄alkyl)₂, NHCO₂(C₁₄ alkyl), NHSO₂(C₁₋₄ alkyl), pyrazolyl, andmorpholinyl; alternatively, R¹² and R¹³, together with the carbon atomsto which they are attached, combine to form a 5- to 6-memberedcarbocyclic ring or a 5- to 6-membered saturated heterocyclic ringcomprising: carbon atoms and 1-2 oxygen atoms; R¹⁴ is independentlyselected from the group consisting of: H and C₁₄ alkoxy; R^(b) is, ateach occurrence, independently selected from the group consisting of:halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₁₀ haloalkoxy,—O(CH₂)_(s)O(C₁₋₆ alkyl), —CONH(CH₂)₆₋₂₀H, —(CH₂)_(m)(C₃₋₆ cycloalkyl),—(CH₂)_(m)(C₄₋₆ cycloalkenyl), —O(CH₂)_(m)(C₃₋₆ cycloalkyl), phenoxy,benzoxy, morpholinyl, 2-C₁₋₄ alkoxy-pyridin-5-yl, pyrimidin-5-yl,pyrazin-2-yl and —O-pyrimidinyl; and R^(c) is, at each occurrence,independently selected from the group consisting of: C₃₋₆ cycloalkylsubstituted with 0-2 R^(d), —(CH₂)_(m)-(phenyl substituted with 0-3R^(d)), and a heteroaryl selected from: oxazolyl, isoxazolyl, thiazolyl,pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, andpyrazinyl; wherein said heteroaryl is substituted with 0-2 R^(d).
 3. Acompound according to claim 2, wherein: R¹ is

R⁶ is independently selected from the group consisting of: OPh,—CONH(C₃₋₆ cycloalkyl), —CONHPh, —CONH-(2-halo-Ph), —CONH-(3-halo-Ph),—CONH-(4-halo-Ph), —CONH-(4-C₁₋₄ alkyl-Ph), —CONH(4-OH-Ph),—CONH-(3-C₁₋₄ alkoxy-Ph), —CONH-(4-C₁₋₄ alkoxy-Ph), —CONH-(4-C₁₋₄haloalkyl-Ph), —CONH-(4-C₁₋₄ haloalkoxy-Ph), —CONH-(4-CN-Ph),—CONH-(4-tetrazolyl-Ph), —CONH-(3-halo-4-C₁₋₄ alkyl-Ph),—CONH-(3-halo-4-C₁₋₄ alkoxy-Ph), —CONH(CH₂)₂Ph, —CONH(4-(4-C₁₋₄alkoxy-Ph)-thiazol-2-yl), —CONH(1-C₁₋₄ alkyl-pyrazol-3-yl), —CONH(5-C₁₋₄alkoxy-pyrid-2-yl), —CONH(6-C₁₋₄ alkoxy-pyrid-3-yl), —CONH(5-C₁₋₄alkoxy-pyrazin-2-yl), —CONH(6-C₁₋₄ alkoxy-pyridazin-3-yl),—NHCO(CH₂)SO₂(C₁₋₄ alkyl), —NHCOPh, —NHCO(2-C₁₋₄ alkyl-Ph), —NHCO(3-C₁₋₄alkyl-Ph), —NHCO(4-C₁₋₄ alkyl-Ph), —NHCO(2-halo-Ph), —NHCO(3-halo-Ph),—NHCO(2-C₁₋₄ haloalkyl-Ph), —NHCO(2-C₁₋₄ haloalkoxy-Ph),—NHCO(2-halo-4-halo-Ph), —NHCO(2-halo-5-halo-Ph), —NHCO(oxazolyl),—NHCO(isoxazolyl), —NHCO(3-C₁₋₄ alkyl-isoxazol-5-yl), —NHCO(4-C₁₋₄alkyl-isoxazol-5-yl), —NHCO(3-C₁₋₄ alkoxy-isoxazol-5-yl), —NHCO(4-C₁₋₄alkoxy-isoxazol-5-yl), —NHCO(3-halo-isoxazol-5-yl),—NHCO(3-OBn-isoxazol-5-yl), —NHCO(3-(2-halo-Ph)-isoxazol-5-yl),—NHCO(3-(3-halo-Ph)-isoxazol-5-yl), —NHCO(5-C₁₋₄ alkyl-1H-pyrazol-3-yl),imidazolyl, —NHCO(5-C₁₋₄ alkyl-1,3,4-oxadiazol-2-yl), —NHCO(1-C₁₋₄alkyl-1,2,3-triazol-4-yl), —NHCO(6-C₁₋₄ alkoxy-pyrid-3-yl),—NHCO(pyrazinyl), —NHCO(6-halo-pyridazin-3-yl), 5-C₁₋₄haloalkyl-1,3,4-oxadiazol-2-yl, 3-NO₂-1H-1,2,4-triazol-1-yl, tetrazolyland 5-C₁₋₄ alkyl-tetrazol-1-yl; R^(b) is independently selected from thegroup consisting of: halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₈haloalkoxy, —CONH(CH₂)₆₋₂₀H, C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl,—O(CH₂)_(m)(C₃₋₆ cycloalkyl), phenoxy, benzoxy, pyrimidinyl, pyrazinyland —O-pyrimidinyl; and R^(g) is independently selected from the groupconsisting of: halo and C₁₋₄ alkyl.
 4. A compound according to claim 3,wherein: R² is independently selected from the group consisting of: CF₃and Me; R³ is independently selected from the group consisting of: H andF; R⁴ is independently selected from the group consisting of: H and F;R⁶ is independently selected from the group consisting of: OPh,—CONH(cyclopropyl), —CONH(cyclobutyl), —CONH(cyclopentyl),—CONH(cyclohexyl), —CONHPh, —CONH(4-F-Ph), —CONH(2-Cl-Ph),—CONH(4-Cl-Ph), —CONH(4-Me-Ph), —CONH(4-OH-Ph), —CONH(3-OMe-Ph),—CONH(4-OMe-Ph), —CONH(4-CF₃-Ph), —CONH(4-OCF₃-Ph),—CONH(1-Me-pyrazol-3-yl), —CONH(4-(1H-tetrazol-2-yl)-Ph),—CONH(4-(2H-tetrazol-5-yl)-Ph), —CONH(3-F-4-Me-Ph), —CONH(3-F-4-OMe-Ph),—CONH(CH₂)₂Ph, —CONH(5-OMe-pyrid-2-yl), —CONH(6-OMe-pyrid-3-yl),—CONH(5-OMe-pyrazin-2-yl), —CONH(6-OMe-pyridazin-3-yl), —NHCO(CH₂)SO₂Me,—NHCOPh, —NHCO(2-Me-Ph), —NHCO(3-Me-Ph), —NHCO(4-Me-Ph), —NHCO(2-Cl-Ph),—NHCO(3-Cl-Ph), —NHCO(2-C₁₋₄—F-Ph), —NHCO(2-C₁₋₅-F-Ph),—NHCO(isoxazol-5-yl), —NHCO(3-Me-isoxazol-5-yl),—NHCO(4-Me-isoxazol-5-yl), —NHCO(3-OMe-isoxazol-5-yl),—NHCO(3-Br-isoxazol-5-yl), —NHCO(3-(2-Cl-Ph)-isoxazol-5-yl),—NHCO(3-(3-F-Ph)-isoxazol-5-yl), —NHCO(3-OBn-isoxazol-5-yl),1H-imidazol-1-yl, —NHCO(5-Me-1,3,4-oxadiazol-2-yl),—NHCO(1-Me-1,2,3-triazol-4-yl), —NHCO(6-OMe-pyrid-3-yl),—NHCO(6-Cl-pyridazin-3-yl), 5-CF₃-1,3,4-oxadiazol-2-yl,1H-tetrazol-1-yl, 1H-tetrazol-3-yl, and 2H-tetrazol-5-yl; R¹¹ and R¹⁵are independently selected from the group consisting of: H, Me, F, andCl; R¹² is independently selected from the group consisting of: H, F,Cl, Me and OMe; R¹³ is independently selected from the group consistingof: H, F, Cl, Br, Me, OMe, OEt, CH₂OMe, CF₃, CH₂CF₃, OCHF₂, OCF₃, CN,N(Me)₂, cyclopropyl and cyclopropylmethyl; alternatively, R¹² and R¹³,together with the carbon atoms to which they are attached, combine toform a 5- to 6-membered carbocyclic ring or a 5- to 6-membered saturatedheterocyclic ring comprising: carbon atoms and 1-2 oxygen atoms; R¹⁴ isH; R^(b) is, at each occurrence, independently selected from the groupconsisting of: n-pentyl, methoxy, n-butoxy, i-butoxy, i-pentoxy,—O(CH₂)₁₋₆CF₃, —O(CH₂)₁₋₄CF₂CF₃, —CONH(CH₂)₆₋₂₀H, cyclopropyl,cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, —O(CH₂)₂(cyclopentyl), phenoxy,benzoxy, pyrimidin-5-yl, pyrazin-2-yl and —O-pyrimidin-2-yl; and R^(g)is F.
 5. A compound according to claim 2, wherein: R¹³ is independentlyselected from the group consisting of: H, halo, C₁₋₄ alkyl substitutedwith 0-1 C₁₋₄ alkoxy, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CNor C₃₋₄ cycloalkyl.
 6. A compound according to claim 5, wherein: R¹ isindependently


7. A compound according to claim 6, wherein: R^(b) is independentlyselected from: —O(CH₂)₁₋₆CF₃, and —O(CH₂)₁₋₄CF₂CF₃.
 8. A compoundaccording to claim 7, wherein: R⁶ is independently 5-membered nitrogenheteroaryl.
 9. A compound according to claim 8, wherein: R⁶ isindependently 1H-imidazol-1-yl, 1H-tetrazol-1-yl, 1H-tetrazol-3-yl, or2H-tetrazol-5-yl.
 10. A compound selected from:

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof.
 11. A compound having the following formula:

or a tautomer, or a pharmaceutically acceptable salt thereof.
 12. Acompound according to claim 11, wherein the compound has the followingformula:


13. A compound having the following formula:

or a tautomer, or a pharmaceutically acceptable salt thereof.
 14. Acompound according to claim 13, wherein the compound has the followingformula:


15. A compound having the following formula:

or a tautomer, or a pharmaceutically acceptable salt thereof.
 16. Acompound according to claim 15, wherein the compound has the followingformula:


17. A pharmaceutical composition, comprising: a pharmaceuticallyacceptable carrier and a compound of claim 1, or a stereoisomer, atautomer, or a pharmaceutically acceptable salt thereof.
 18. Thepharmaceutical composition according to claim 17, further comprising oneor more other suitable therapeutic agents selected from: anti-diabeticagents, anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents, lipid loweringagents, anorectic agents, and appetite suppressants.
 19. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of claim 10, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 20. The pharmaceuticalcomposition according to claim 19, further comprising one or more othersuitable therapeutic agents selected from: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents, lipid loweringagents, anorectic agents, and appetite suppressants.
 21. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of claim 11, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 22. The pharmaceuticalcomposition according to claim 21, further comprising one or more othersuitable therapeutic agents selected from: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents, lipid loweringagents, anorectic agents, and appetite suppressants.
 23. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of claim 12, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 24. The pharmaceuticalcomposition according to claim 23, further comprising one or more othersuitable therapeutic agents selected from: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents, lipid loweringagents, anorectic agents, and appetite suppressants.
 25. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of claim 13, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 26. The pharmaceuticalcomposition according to claim 25, further comprising one or more othersuitable therapeutic agents selected from: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents, lipid loweringagents, anorectic agents, and appetite suppressants.
 27. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of claim 14, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 28. The pharmaceuticalcomposition according to claim 27, further comprising one or more othersuitable therapeutic agents selected from: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents, lipid loweringagents, anorectic agents, and appetite suppressants.
 29. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of claim 15, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 30. The pharmaceuticalcomposition according to claim 29, further comprising one or more othersuitable therapeutic agents selected from: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents, lipid loweringagents, anorectic agents, and appetite suppressants.
 31. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of claim 16, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 32. The pharmaceuticalcomposition according to claim 31, further comprising one or more othersuitable therapeutic agents selected from: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents, lipid loweringagents, anorectic agents, and appetite suppressants.
 33. A method forthe treatment of diabetes, hyperglycemia, impaired glucose tolerance,gestational diabetes, insulin resistance, hyperinsulinemia, nonalcoholicfatty liver disease, nonalcoholic steatohepatitis, retinopathy,neuropathy, nephropathy, delayed wound healing, Metabolic Syndrome,obesity, dyslipidemia, and glaucoma, comprising administering to apatient in need of such treatment a therapeutically effective amount ofat least a compound of claim
 1. 34. A method for the treatment ofdiabetes, hyperglycemia, impaired glucose tolerance, gestationaldiabetes, insulin resistance, hyperinsulinemia, nonalcoholic fatty liverdisease, nonalcoholic steatohepatitis, retinopathy, neuropathy,nephropathy, delayed wound healing, Metabolic Syndrome, obesity,dyslipidemia, and glaucoma, comprising administering to a patient inneed of such treatment a therapeutically effective amount of at least acompound of claim
 10. 35. A method for the treatment of diabetes,hyperglycemia, impaired glucose tolerance, gestational diabetes, insulinresistance, hyperinsulinemia, nonalcoholic fatty liver disease,nonalcoholic steatohepatitis, retinopathy, neuropathy, nephropathy,delayed wound healing, Metabolic Syndrome, obesity, dyslipidemia, andglaucoma, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of at least a compound ofclaim
 11. 36. A method for the treatment of diabetes, hyperglycemia,impaired glucose tolerance, gestational diabetes, insulin resistance,hyperinsulinemia, nonalcoholic fatty liver disease, nonalcoholicsteatohepatitis, retinopathy, neuropathy, nephropathy, delayed woundhealing, Metabolic Syndrome, obesity, dyslipidemia, and glaucoma,comprising administering to a patient in need of such treatment atherapeutically effective amount of at least a compound of claim
 12. 37.A method for the treatment of diabetes, hyperglycemia, impaired glucosetolerance, gestational diabetes, insulin resistance, hyperinsulinemia,nonalcoholic fatty liver disease, nonalcoholic steatohepatitis,retinopathy, neuropathy, nephropathy, delayed wound healing, MetabolicSyndrome, obesity, dyslipidemia, and glaucoma, comprising administeringto a patient in need of such treatment a therapeutically effectiveamount of at least a compound of claim
 13. 38. A method for thetreatment of diabetes, hyperglycemia, impaired glucose tolerance,gestational diabetes, insulin resistance, hyperinsulinemia, nonalcoholicfatty liver disease, nonalcoholic steatohepatitis, retinopathy,neuropathy, nephropathy, delayed wound healing, Metabolic Syndrome,obesity, dyslipidemia, and glaucoma, comprising administering to apatient in need of such treatment a therapeutically effective amount ofat least a compound of claim
 14. 39. A method for the treatment ofdiabetes, hyperglycemia, impaired glucose tolerance, gestationaldiabetes, insulin resistance, hyperinsulinemia, nonalcoholic fatty liverdisease, nonalcoholic steatohepatitis, retinopathy, neuropathy,nephropathy, delayed wound healing, Metabolic Syndrome, obesity,dyslipidemia, and glaucoma, comprising administering to a patient inneed of such treatment a therapeutically effective amount of at least acompound of claim
 15. 40. A method for the treatment of diabetes,hyperglycemia, impaired glucose tolerance, gestational diabetes, insulinresistance, hyperinsulinemia, nonalcoholic fatty liver disease,nonalcoholic steatohepatitis, retinopathy, neuropathy, nephropathy,delayed wound healing, Metabolic Syndrome, obesity, dyslipidemia, andglaucoma, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of at least a compound ofclaim 16.